Inhibitors of histone deacetylase

ABSTRACT

The invention relates to the inhibition of histone deacetylase. The invention provides compounds and methods for inhibiting histone deacetylase enzymatic activity. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.

This application claims the benefit of U.S. Provisional Application No.60/391,728, filed Jun. 26, 2002, and U.S. Provisional Application No.60/322,402, filed Sep. 14, 2001.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the inhibition of histone deacetylase. Moreparticularly, the invention relates to compounds and methods forinhibiting histone deacetylase enzymatic activity.

2. Summary of the Related Art

In eukaryotic cells, nuclear DNA associates with histones to form acompact complex called chromatin. The histones constitute a family ofbasic proteins which are generally highly conserved across eukaryoticspecies. The core histones, termed H2A, H2B, H3, and H4, associate toform a protein core. DNA winds around this protein core, with the basicamino acids of the histones interacting with the negatively chargedphosphate groups of the DNA. Approximately 146 base pairs of DNA wraparound a histone core to make up a nucleosome particle, the repeatingstructural motif of chromatin.

Csordas, Biochem. J., 286: 23-38 (1990) teaches that histones aresubject to posttranslational acetylation of the α,ε-amino groups ofN-terminal lysine residues, a reaction that is catalyzed by histoneacetyl transferase (HAT1). Acetylation neutralizes the positive chargeof the lysine side chain, and is thought to impact chromatin structure.Indeed, Taunton et al., Science, 272: 408-411 (1996), teaches thataccess of transcription factors to chromatin templates is enhanced byhistone hyperacetylation. Taunton et al. further teaches that anenrichment in underacetylated histone H4 has been found intranscriptionally silent regions of the genome.

Histone acetylation is a reversible modification, with deacetylationbeing catalyzed by a family of enzymes termed histone deacetylases(HDACs). Grozinger et al., Proc. Natl. Acad. Sci. USA, 96: 4868-4873(1999), teaches that HDACs is divided into two classes, the firstrepresented by yeast Rpd3-like proteins, and the second represented byyeast Hda1-like proteins. Grozinger et al. also teaches that the humanHDAC1, HDAC2, and HDAC3 proteins are members of the first class ofHDACs, and discloses new proteins, named HDAC4, HDAC5, and HDAC6, whichare members of the second class of HDACs. Kao et al., Genes & Dev., 14:55-66 (2000), discloses HDAC7, a new member of the second class ofHDACs. Van den Wyngaert, FEBS, 478: 77-83 (2000) discloses HDAC8, a newmember of the first class of HDACs.

Richon et al., Proc. Natl. Acad. Sci. USA, 95: 3003-3007 (1998),discloses that HDAC activity is inhibited by trichostatin A (TSA), anatural product isolated from Streptomyces hygroscopicus, and by asynthetic compound, suberoylanilide hydroxamic acid (SAHA). Yoshida andBeppu, Exper. Cell Res., 177: 122-131 (1988), teaches that TSA causesarrest of rat fibroblasts at the G₁ and G₂ phases of the cell cycle,implicating HDAC in cell cycle regulation. Indeed, Finnin et al.,Nature, 401: 188-193 (1999), teaches that TSA and SAHA inhibit cellgrowth, induce terminal differentiation, and prevent the formation oftumors in mice. Suzuki et al., U.S. Pat. No. 6,174,905, EP 0847992, JP258863/96, and Japanese Application No. 10138957, disclose benzamidederivatives that induce cell differentiation and inhibit HDAC. Delormeet al., WO 01/38322 and PCT IB01/00683, disclose additional compoundsthat serve as HDAC inhibitors.

The molecular cloning of gene sequences encoding proteins with HDACactivity has established the existence of a set of discrete HDAC enzymeisoforms. Grozinger et al., Proc. Natl. Acad. Sci. USA, 96:4868-4873(1999), teaches that HDACs may be divided into two classes, the firstrepresented by yeast Rpd3-like proteins, and the second represented byyeast Hda1-like proteins. Grozinger et al. also teaches that the humanHDAC-1, HDAC-2, and HDAC-3 proteins are members of the first class ofHDACs, and discloses new proteins, named HDAC-4, HDAC-5, and HDAC-6,which are members of the second class of HDACs. Kao et al., GeneDevelopment 14:55-66 (2000), discloses an additional member of thissecond class, called HDAC-7. More recently, Hu, E. et al. J. Bio. Chem.275:15254-13264 (2000) discloses the newest member of the first class ofhistone deacetylases, HDAC-8. It has been unclear what roles theseindividual HDAC enzymes play.

These findings suggest that inhibition of HDAC activity represents anovel approach for intervening in cell cycle regulation and that HDACinhibitors have great therapeutic potential in the treatment of cellproliferative diseases or conditions. To date, few inhibitors of histonedeacetylase are known in the art. There is thus a need to identifyadditional HDAC inhibitors and to identify the structural featuresrequired for potent HDAC inhibitory activity.

BRIEF SUMMARY OF THE INVENTION

The invention provides compounds and methods for treating cellproliferative diseases. The invention provides new inhibitors of histonedeacetylase enzymatic activity.

In a first aspect, the invention provides compounds that are useful asinhibitors of histone deacetylase.

In a second aspect, the invention provides a composition comprising aninhibitor of histone deacetylase according to the invention and apharmaceutically acceptable carrier, excipient, or diluent.

In a third aspect, the invention provides a method of inhibiting histonedeacetylase in a cell, comprising contacting a cell in which inhibitionof histone deacetylase is desired with an inhibitor of histonedeacetylase of the invention.

The foregoing merely summarizes certain aspects of the invention and isnot intended to be limiting in nature. These aspects and other aspectsand embodiments are described more fully below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the antitumor activity of compound 106 in anHCT 116 human colorectal tumor model.

FIGS. 2-11 show additional data for other compounds used in the in vivoexperiment described in Assay Example 2.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention provides compounds and methods for inhibiting histonedeacetylase enzymatic activity. The invention also provides compositionsand methods for treating cell proliferative diseases and conditions. Thepatent and scientific literature referred to herein establishesknowledge that is available to those with skill in the art. The issuedpatents, applications, and references that are cited herein are herebyincorporated by reference to the same extent as if each was specificallyand individually indicated to be incorporated by reference. In the caseof inconsistencies, the present disclosure will prevail.

For purposes of the present invention, the following definitions will beused (unless expressly stated otherwise):

As used herein, the terms “histone deacetylase” and “HDAC” are intendedto refer to any one of a family of enzymes that remove acetyl groupsfrom the, -amino groups of lysine residues at the N-terminus of ahistone. Unless otherwise indicated by context, the term “histone” ismeant to refer to any histone protein, including H1, H2A, H2B, H3, H4,and H5, from any species. Preferred histone deacetylases include class Iand class II enzymes. Preferably the histone deacetylase is a humanHDAC, including, but not limited to, HDAC-1, HDAC-2, HDAC-3, HDAC-4,HDAC-5, HDAC-6, HDAC-7, and HDAC-8. In some other preferred embodiments,the histone deacetylase is derived from a protozoal or fungal source.

The terms “histone deacetylase inhibitor” and “inhibitor of histonedeacetylase” are used to identify a compound having a structure asdefined herein, which is capable of interacting with a histonedeacetylase and inhibiting its enzymatic activity. “Inhibiting histonedeacetylase enzymatic activity” means reducing the ability of a histonedeacetylase to remove an acetyl group from a histone. In some preferredembodiments, such reduction of histone deacetylase activity is at leastabout 50%, more preferably at least about 75%, and still more preferablyat least about 90%. In other preferred embodiments, histone deacetylaseactivity is reduced by at least 95% and more preferably by at least 99%.

Preferably, such inhibition is specific, i.e., the histone deacetylaseinhibitor reduces the ability of a histone deacetylase to remove anacetyl group from a histone at a concentration that is lower than theconcentration of the inhibitor that is required to produce another,unrelated biological effect. Preferably, the concentration of theinhibitor required for histone deacetylase inhibitory activity is atleast 2-fold lower, more preferably at least 5-fold lower, even morepreferably at least 10-fold lower, and most preferably at least 20-foldlower than the concentration required to produce an unrelated biologicaleffect.

For simplicity, chemical moieties are defined and referred to throughoutprimarily as univalent chemical moieties (e.g., alkyl, aryl, etc.).Nevertheless, such terms are also used to convey correspondingmultivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, while an “alkyl” moietygenerally refers to a monovalent radical (e.g. CH₃—CH₂—), in certaincircumstances a bivalent linking moiety can be “alkyl,” in which casethose skilled in the art will understand the alkyl to be a divalentradical (e.g., —CH₂—CH₂—), which is equivalent to the term “alkylene.”(Similarly, in circumstances in which a divalent moiety is required andis stated as being “aryl,” those skilled in the art will understand thatthe term “aryl” refers to the corresponding divalent moiety, arylene.)All atoms are understood to have their normal number of valences forbond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 forS, depending on the oxidation state of the S). On occasion a moiety maydefined, for example, as (A)_(a)-B—, wherein a is 0 or 1. In suchinstances, when a is 0 the moiety is B— and when a is 1 the moiety isA-B—. Also, a number of moieties disclosed herein exist in multipletautomeric forms, all of which are intended to be encompassed by anygiven tautomeric structure.

The term “hydrocarbyl” refers to a straight, branched, or cyclic alkyl,alkenyl, or alkynyl, each as defined herein. A “C₀” hydrocarbyl is usedto refer to a covalent bond. Thus, “C₀-C₃-hydrocarbyl” includes acovalent bond, methyl, ethyl, propyl, and cyclopropyl.

The term “alkyl” as employed herein refers to straight and branchedchain aliphatic groups having from 1 to 12 carbon atoms, preferably 1-8carbon atoms, and more preferably 1-6 carbon atoms, which is optionallysubstituted with one, two or three substituents. Preferred alkyl groupsinclude, without limitation, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. A “C₀” alkyl (as in“C₀-C₃-alkyl”) is a covalent bond (like “C₀” hydrocarbyl).

The term “alkenyl” as used herein means an unsaturated straight orbranched chain aliphatic group with one or more carbon-carbon doublebonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms,and more preferably 2-6 carbon atoms, which is optionally substitutedwith one, two or three substituents. Preferred alkenyl groups include,without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

The term “alkynyl” as used herein means an unsaturated straight orbranched chain aliphatic group with one or more carbon-carbon triplebonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms,and more preferably 2-6 carbon atoms, which is optionally substitutedwith one, two or three substituents. Preferred alkynyl groups include,without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

An “alkylene,” “alkenylene,” or “alkynylene” group is an alkyl, alkenyl,or alkynyl group, as defined hereinabove, that is positioned between andserves to connect two other chemical groups. Preferred alkylene groupsinclude, without limitation, methylene, ethylene, propylene, andbutylene. Preferred alkenylene groups include, without limitation,ethenylene, propenylene, and butenylene. Preferred alkynylene groupsinclude, without limitation, ethynylene, propynylene, and butynylene.

The term “cycloalkyl” as employed herein includes saturated andpartially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons,preferably 3 to 8 carbons, and more preferably 3 to 6 carbons, whereinthe cycloalkyl group additionally is optionally substituted. Preferredcycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, andcyclooctyl.

The term “heteroalkyl” refers to an alkyl group, as defined hereinabove,wherein one or more carbon atoms in the chain are replaced by aheteratom selected from the group consisting of O, S, and N.

An “aryl” group is a C₆-C₁₄ aromatic moiety comprising one to threearomatic rings, which is optionally substituted. Preferably, the arylgroup is a C₆-C₁₀ aryl group. Preferred aryl groups include, withoutlimitation, phenyl, naphthyl, anthracenyl, and fluorenyl. An “aralkyl”or “arylalkyl” group comprises an aryl group covalently linked to analkyl group, either of which may independently be optionally substitutedor unsubstituted. Preferably, the aralkyl group is(C₁-C₆)alk(C₆-C₁₀)aryl, including, without limitation, benzyl,phenethyl, and naphthylmethyl.

A “heterocyclyl” or “heterocyclic” group is a ring structure having fromabout 3 to about 8 atoms, wherein one or more atoms are selected fromthe group consisting of N, O, and S. The heterocyclic group isoptionally substituted on carbon at one or more positions. Theheterocyclic group is also independently optionally substituted onnitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl,arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, or onsulfur with oxo or lower alkyl. Preferred heterocyclic groups include,without limitation, epoxy, aziridinyl, tetrahydrofuranyl, pyrrolidinyl,piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, oxazolidinonyl,and morpholino. In certain preferred embodiments, the heterocyclic groupis fused to an aryl, heteroaryl, or cycloalkyl group. Examples of suchfused heterocyles include, without limitation, tetrahydroquinoline anddihydrobenzofuran. Specifically excluded from the scope of this term arecompounds having adjacent annular O and/or S atoms.

As used herein, the term “heteroaryl” refers to groups having 5 to 14ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 πelectrons shared in a cyclic array; and having, in addition to carbonatoms, from one to three heteroatoms per ring selected from the groupconsisting of N, O, and S. A “heteroaralkyl” or “heteroarylalkyl” groupcomprises a heteroaryl group covalently linked to an alkyl group, eitherof which is independently optionally substituted or unsubstituted.Preferred heteroalkyl groups comprise a C₁-C₆ alkyl group and aheteroaryl group having 5, 6, 9, or 10 ring atoms. Specifically excludedfrom the scope of this term are compounds having adjacent annular Oand/or S atoms. Examples of preferred heteroaralkyl groups includepyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl,imidazolylmethyl, imidazolylethyl, thiazolylmethyl, and thiazolylethyl.Specifically excluded from the scope of this term are compounds havingadjacent annular O and/or S atoms.

An “arylene,” “heteroarylene,” or “heterocyclylene” group is an aryl,heteroaryl, or heterocyclyl group, as defined hereinabove, that ispositioned between and serves to connect two other chemical groups.

Preferred heterocyclyls and heteroaryls include, but are not limited to,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl.

As employed herein, when a moiety (e.g., cycloalkyl, hydrocarbyl, aryl,heteroaryl, heterocyclic, urea, etc.) is described as “optionallysubstituted” it is meant that the group optionally has from one to four,preferably from one to three, more preferably one or two, non-hydrogensubstituents. Suitable substituents include, without limitation, halo,hydroxy, oxo (e.g., an annular —CH— substituted with oxo is —C(O)—)nitro, halohydrocarbyl, hydrocarbyl, aryl, aralkyl, alkoxy, aryloxy,amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl,carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido,arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, andureido groups. Preferred substituents, which are themselves not furthersubstituted (unless expressly stated otherwise) are:

-   -   (a) halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino,        guanidino,    -   (b) C₁-C₅ alkyl or alkenyl or arylalkyl imino, carbamoyl, azido,        carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl,        arylalkyl, C₁-C₈ alkyl, C_(1-C) ₈ alkenyl, C₁-C₈ alkoxy, C₁-C₈        alkoxycarbonyl, aryloxycarbonyl, C₂-C₈ acyl, C₂-C₈ acylamino,        C₁-C₈ alkylthio, arylalkylthio, arylthio, C₁-C₈ alkylsulfinyl,        arylalkylsulfinyl, arylsulfinyl, C₁-C₈ alkylsulfonyl,        arylalkylsulfonyl, arylsulfonyl, C₀-C₆ N-alkyl carbamoyl, C₂-C₁₅        N,N-dialkylcarbamoyl, C₃-C₇ cycloalkyl, aroyl, aryloxy,        arylalkyl ether, aryl, aryl fused to a cycloalkyl or heterocycle        or another aryl ring, C₃-C₇ heterocycle, or any of these rings        fused or spiro-fused to a cycloalkyl, heterocyclyl, or aryl,        wherein each of the foregoing is further optionally substituted        with one more moieties listed in (a), above; and    -   (c) —(CH₂)_(s)—NR³⁰R³¹, wherein s is from 0 (in which case the        nitrogen is directly bonded to the moiety that is substituted)        to 6, and R³⁰ and R³¹ are each independently hydrogen, cyano,        oxo, carboxamido, amidino, C₁-C₈ hydroxyalkyl, C₁-C₃ alkylaryl,        aryl-C₁-C₃ alkyl, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkoxy,        C₁-C₈ alkoxycarbonyl, aryloxycarbonyl, aryl-C₁-C₃        alkoxycarbonyl, C₂-C₈ acyl, C₁-C₈ alkylsulfonyl,        arylalkylsulfonyl, arylsulfonyl, aroyl, aryl, cycloalkyl,        heterocyclyl, or heteroaryl, wherein each of the foregoing is        further optionally substituted with one more moieties listed in        (a), above; or    -   R³⁰ and R³¹ taken together with the N to which they are attached        form a heterocyclyl or heteroaryl, each of which is optionally        substituted with from 1 to 3 substituents from (a), above.

In addition, substituents on cyclic moieties (i.e., cycloalkyl,heterocyclyl, aryl, heteroaryl) include 5-6 membered mono- and 10-12membered bi-cyclic moieties fused to the parent cyclic moiety to form abi- or tri-cyclic fused ring system. For example, an optionallysubstituted phenyl includes the following:

A “halohydrocarbyl” is a hydrocarbyl moiety in which from one to allhydrogens have been replaced with one or more halo.

The term “halogen” or “halo” as employed herein refers to chlorine,bromine, fluorine, or iodine. As herein employed, the term “acyl” refersto an alkylcarbonyl or arylcarbonyl substituent. The term “acylamino”refers to an amide group attached at the nitrogen atom (i.e., R—CO—NH—).The term “carbamoyl” refers to an amide group attached at the carbonylcarbon atom (i.e., NH₂—CO—). The nitrogen atom of an acylamino orcarbamoyl substituent is additionally substituted. The term“sulfonamido” refers to a sulfonamide substituent attached by either thesulfur or the nitrogen atom. The term “amino” is meant to include NH₂,alkylamino, arylamino, and cyclic amino groups. The term “ureido” asemployed herein refers to a substituted or unsubstituted urea moiety.

The term “radical” as used herein means a chemical moiety comprising oneor more unpaired electrons.

A moiety that is substituted is one in which one or more hydrogens havebeen independently replaced with another chemical substituent. As anon-limiting example, substituted phenyls include 2-flurophenyl,3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2-fluor-3-propylphenyl. Asanother non-limiting example, substituted n-octyls include 2,4dimethyl-5-ethyl-octyl and 3-cyclopentyl-octyl. Included within thisdefinition are methylenes (—CH₂—) substituted with oxygen to formcarbonyl-CO—).

An “unsubstituted” moiety as defined above (e.g., unsubstitutedcycloalkyl, unsubstituted heteroaryl, etc.) means that moiety as definedabove that does not have any of the optional substituents for which thedefinition of the moiety (above) otherwise provides. Thus, for example,while an “aryl” includes phenyl and phenyl substituted with a halo,“unsubstituted aryl” does not include phenyl substituted with a halo.

Preferred embodiments of a particular genus of compounds of theinvention include combinations of preferred embodiments. For example,paragraph [0042] identifies a preferred Ay¹ and paragraph [0046]identifies preferred Ar¹ (both for compound (1) of paragraph [0041]).Thus, another preferred embodiment includes those compounds of formula(1) in paragraph [0041] in which Ay¹ is as defined in paragraph [0042]and Ar¹ is as defined in paragraph [0046].

Compounds

In a first aspect, the invention provides novel inhibitors of histonedeacetylase. In a first embodiment, the novel inhibitors of histonedeacetylase are represented by formula (1):

and pharmaceutically acceptable salts thereof, wherein

-   -   R³ and R⁴ are independently selected from the group consisting        of hydrogen, L¹, Cy¹, and -L¹-Cy¹, wherein        -   L¹ is C₁-C₆ alkyl, C₂-C₆ heteroalkyl, or C₃-C₆ alkenyl; and        -   Cy¹ is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each            of which optionally is substituted, and each of which            optionally is fused to one or more aryl or heteroaryl rings,            or to one or more saturated or partially unsaturated            cycloalkyl or heterocyclic rings, each of which rings            optionally is substituted; or    -   R³ and R⁴ are taken together with the adjacent nitrogen atom to        form a 5-, 6-, or 7-membered ring, wherein the ring atoms are        independently selected from the group consisting of C, O, S, and        N, and wherein the ring optionally is substituted, and        optionally forms part of a bicyclic ring system, or optionally        is fused to one or more aryl or heteroaryl rings, or to one or        more saturated or partially unsaturated cycloalkyl or        heterocyclic rings, each of which rings and ring systems        optionally is substituted;    -   Y¹ is selected from the group consisting of —N(R¹)(R²),        —CH₂—C(O)—N(R¹)(R²), halogen, and hydrogen, wherein        -   R¹ and R² are independently selected from the group            consisting of hydrogen, L¹, Cy¹, and -L¹-Cy¹, wherein        -   L¹ is C₁-C₆ alkyl, C₂-C₆ heteroalkyl, or C₃-C₆ alkenyl; and        -   Cy¹ is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each            of which optionally is substituted, and each of which            optionally is fused to one or more aryl or heteroaryl rings,            or to one or more saturated or partially unsaturated            cycloalkyl or heterocyclic rings, each of which rings            optionally is substituted; or        -   R¹ and R² are taken together with the adjacent nitrogen atom            to form a 5-, 6-, or 7-membered ring, wherein the ring atoms            are independently selected from the group consisting of C,            O, S, and N, and wherein the ring optionally is substituted,            and optionally may form part of a bicyclic ring system, or            optionally is fused to one or more aryl or heteroaryl rings,            or to one or more saturated or partially unsaturated            cycloalkyl or heterocyclic rings, each of which rings and            ring systems optionally is substituted;    -   Y² is a chemical bond or N(R⁰), where R⁰ is selected from the        group consisting of hydrogen, alkyl, aryl, aralkyl, and acyl;    -   Ak¹ is C₁-C₆ alkylene, C₁-C₆-heteroalkylene (preferably, in        which one —CH₂— is replaced with —NH—, and more preferably        —NH—CH₂—), C₂-C₆ alkenylene or C₂-C₆ alkynylene;    -   Ar¹ is arylene or heteroarylene, either of which optionally is        substituted; and    -   Z¹ is selected from the group consisting of

-   -   wherein Ay¹ is aryl or heteroaryl, which optionally is        substituted.

Preferably in the compounds according to paragraph [0041], Ay¹ is phenylor thienyl, each substituted with —OH or —NH₂.

More preferably in the compounds according to paragraph [0041], Ay¹ isoptionally amino- or hydroxy-substituted phenyl or thienyl, wherein theamino or hydroxy substituent is preferably ortho to the nitrogen towhich Ay² is attached.

More preferably in the compounds according to paragraph [0041], Ay¹ isortho aniline, ortho phenol, 3-amino-2-thienyl, or 3-hydroxy-2-thienyl,and tautomers thereof.

In some preferred embodiments of the compounds according to paragraph[0041], Z¹ is

In some preferred embodiments of the compounds according to paragraph[0041], Ar¹ is phenylene. In some embodiments, Ak¹ is alkylene,preferably methylene. In some preferred embodiments, Y² is —NH—. In somepreferred embodiments, Y¹ is —N(R¹)(R²) or —CH₂—C(O)—N(R¹)(R²).

In some embodiments of the compounds according to paragraph [0041], R¹and R² are each independently selected from the group consisting ofhydrogen, L¹, Cy¹, and -L¹-Cy¹. In some embodiments, R¹ and/or R² ishydrogen. In other embodiments, R¹ and/or R² is alkyl or alkenyl,preferably allyl. In still other embodiments, R¹ and/or R² is aryl,heteroaryl, aralkyl, or heteroaralkyl, the rings of each of whichoptionally is substituted and optionally is fused to one or more arylrings. Some preferred aryl, heteroaryl, aralkyl, and heteroaralkylgroups comprise a phenyl, pyridyl, or pyrrolyl ring. In still otherembodiments, R¹ and/or R² is cycloalkyl, e.g., cyclopropyl, cyclopentyl,or cyclohexyl, which optionally is substituted and optionally is fusedto one or more aryl rings.

In some embodiments of the compounds according to paragraph [0041], R³and R⁴ are each independently selected from the group consisting ofhydrogen, L¹, Cy¹, and -L¹-Cy¹. In some embodiments, R³ and/or R⁴ ishydrogen. In other embodiments, R³ and/or R⁴ is alkyl or alkenyl,preferably allyl. In still other embodiments, R³ and/or R⁴ is aryl,heteroaryl, aralkyl, or heteroaralkyl, the rings of each of whichoptionally is substituted and optionally is fused to one or more arylrings. Some preferred aryl, heteroaryl, aralkyl, and heteroaralkylgroups comprise a phenyl, pyridyl, or pyrrolyl ring. In still otherembodiments, R³ and/or R⁴ is cycloalkyl, e.g., cyclopropyl, cyclopentyl,or cyclohexyl, which optionally is substituted and optionally is fusedto one or more aryl rings.

As set forth above, L¹ is C₁-C₆ alkyl, C₂-C₆ heteroalkyl, or C₃-C₆alkenyl. However, one skilled in the art will understand that when L¹ isnot a terminal group, then L¹ is C₁-C₆ alkylene, C₂-C₆ heteroalkylene,or C₃-C₆ alkenylene. In some embodiments, L¹ is alkylene, preferablymethylene or ethylene. In other embodiments, L¹ is alkenyl, preferablyallyl. In some embodiments, Cy¹is the radical of a heterocyclic groupincluding, without limitation, piperidine, pyrrolidine, piperazine, andmorpholine, each of which optionally is substituted and optionally isfused to one or more aryl rings. In other embodiments Cy¹ is cycloalkyl,e.g., cyclopropyl, cyclopentyl, or cyclohexyl. In still otherembodiments, Cy¹ is aryl or heteroaryl, e.g., phenyl, pyridyl, orpyrrolyl, each of which optionally is substituted and optionally isfused to one or more aryl rings. In some embodiments, Cy¹ is fused toone or two benzene rings. In some embodiments, Cy¹ has between one andabout five substituents selected from the group consisting of C₁-C₄alkyl, C₁-C₄ alkoxy, and halo. Examples of preferred substituentsinclude methyl, methoxy, and fluoro.

In some embodiments of the compounds according to paragraph [0041], R¹and R² and/or R³ and R⁴ are taken together with the adjacent nitrogenatom to form a 5- or 6-membered ring, wherein the ring atoms areindependently selected from the group consisting of C, O, and N, andwherein the ring optionally is substituted, and optionally is fused toone or more aryl rings. In some preferred embodiments, R¹ and R² and/orR³ and R⁴ are taken together with the adjacent nitrogen atom to form aring such as, for example, pyrrolidine, piperidine, piperazine, andmorpholine, wherein the ring optionally is substituted, and optionallyis fused to an aryl ring. In some embodiments, the ring comprising R¹and R² or R³ and R⁴ is fused to a benzene ring. In some embodiments, thering comprising R¹ and R² or R³ and R⁴ has a substituent comprising anaryl or cycloalkyl ring, either of which optionally is substituted andoptionally is fused to a cycloalkyl, aryl, heteroaryl, or heterocyclicring. Preferred substituents include, without limitation, phenyl,phenylmethyl, and phenylethyl, the phenyl ring of which optionally isfused to a cycloalkyl, aryl, or heterocyclic ring.

In a preferred embodiment, the HDAC inhibitors of the invention comprisecompounds of formula 1(a):

and pharmaceutically acceptable salts thereof, wherein

-   -   J is C₁-C₃-hydrocarbyl, —N(R²⁰)—, —N(R²⁰)—CH₂—, —O—, or —O—CH₂—;    -   R²⁰ is —H or -Me;    -   X and Y are independently selected from —NH₂, cycloalkyl,        heterocyclyl, aryl, heteroaryl, and A-(C₁-C₆-alkyl)_(n)-B—;        -   A is H, C₁-C₆-alkyloxy, cycloalkyl, heterocyclyl, aryl, or            heteroaryl;        -   B is —NH—, —O—, or a direct bond; and        -   n is 0 (in which case A is directly bonded to B) or 1.

Preferably in the compounds according to paragraph [0051], A is phenyloptionally substituted with one or more moieties selected from halo(preferably chloro) and methoxy, and B is —NH—. In another preferredembodiment, A is selected from cyclopropyl, pyridinyl, and indanyl.

Preferably in the compounds according to paragraph [0051], J is—NH—CH₂—, —O—CH₂—, —N(CH₃)—CH₂—, —CH═CH—, or —CH₂—CH₂—.

Preferably in the compounds according to paragraph [0051], R²⁰ is —H.

In the compounds according to paragraph [0051] X is preferably selectedfrom

—OMe,

—NH₂

and

and Y is preferably selected from

—NH₂,

n-BuNH, MeOCH₂CH₂NH,

—H Me —OMe CH₃(CH₂)₃NH— and CH₃O(CH₂)₂—NH—.

In a more preferred embodiment of the compounds according to paragraph[0051], the HDAC inhibitors of the invention comprise the followingcompounds of formula 1a:

Cpd J X Y 204 —NH—

—NH₂ 207 —OCH₂—

—NH₂ 210 —-NHCH₂—

—H 212 —NHCH₂— —OMe —OMe 214 —NHCH₂—

—OMe 216

—Me 218 —NHCH₂—

—Me 220 —CH═CH— —NH₂ —NH₂— 223 —CH═CH—

—NH₂ 224 —CH₂CH₂— —NH₂ —NH₂ 470 —NHCH₂—

NH₂ 471 —NHCH₂—

472 —NHCH₂—

473 —NHCH₂—

n-BuNH 474 —NHCH₂—

MeO(CH2)₂NH 475 —NHCH₂—

476 —NHCH₂—

477 —NHCH₂—

478 —NHCH₂—

479 —NHCH₂—

480 —NHCH₂—

481 —NHCH₂—

482 —NHCH₂—

483 —NHCH₂—

Me 484 —NHCH₂—

NH₂ and 485 —NHCH₂—

In a second aspect, the novel histone deacetylase inhibitors of theinvention are represented by formula (2):

and pharmaceutically acceptable salts thereof, wherein

-   -   Cy² is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of        which is optionally substituted and each of which is optionally        fused to one or more aryl or heteroaryl rings, or to one or more        saturated or partially unsaturated cycloalkyl or heterocyclic        rings, each of which rings is optionally substituted;    -   X¹ is selected from the group consisting of a covalent bond,        M¹-L²-M¹, and L²-M²-L² wherein        -   L², at each occurrence, is independently selected from the            group consisting of a chemical bond, C₁-C₄ alkylene, C₂-C₄            alkenylene, and C₂-C₄ alkynylene, provided that L² is not a            chemical bond when X¹ is M¹-L²-M¹;        -   M¹, at each occurrence, is independently selected from the            group consisting of —O—, —N(R⁷)—, —S—, —S(O)—, S(O)₂—,            —S(O)₂N(R⁷)—, —N(R⁷)—S(O)₂—, —C(O)—, —C(O)—NH—, —NH—C(O)—,            —NH—C(O)—O— and —O—C(O)—NH—, wherein R⁷ is selected from the            group consisting of hydrogen, alkyl, aryl, aralkyl, acyl,            heterocyclyl, and heteroaryl; and        -   M² is selected from the group consisting of M¹,            heteroarylene, and heterocyclylene, either of which rings            optionally is substituted;    -   Ar² is arylene or heteroarylene, each of which is optionally        substituted;    -   R⁵ and R⁶ are independently selected from the group consisting        of hydrogen, alkyl, aryl, and aralkyl;    -   q is 0 or 1; and    -   Ay² is a 5-6 membered cycloalkyl, heterocyclyl, or heteroaryl        substituted with an amino or hydroxy moiety (preferably these        groups are ortho to the amide nitrogen to which Ay² is attached)        and further optionally substituted;    -   provided that when Cy² is naphthyl, X¹ is —CH₂—, Ar² is phenyl,        R⁵ and R⁶ are H, and q is 0 or 1, Ay² is not phenyl or        o-hydroxyphenyl.

In a preferred embodiment of the compounds according to paragraph[0057], when Ay² is o-phenol optionally substituted by halo, nitro, ormethyl, Ar² is optionally substituted phenyl, X¹ is —O—, —CH₂—, —S—,—S—CH₂—, —S(O)—, —S(O)₂—, —C(O)—, or —OCH₂—, then Cy² is not optionallysubstituted phenyl or naphthyl.

In another preferred embodiment of the compounds according to paragraph[0057], when Ay² is o-anilinyl optionally substituted by halo,C₁-C₆-alkyl, C₁-C₆-alkoxy or —NO₂, q is O, Ar² is phenyl, and X¹ is—CH₂—, then Cy² is not substituted pyridone (which substituents of thepyridone are not limited to substituents described herein).

In another preferred embodiment of the compounds according to paragraph[0057], when X¹ is —CH₂—, Ar² is optionally substituted phenyl, q is 1,and R⁶ is H, then Cy² is not optionally substituted imidazole.

In another preferred embodiment of the compounds according to paragraph[0057], when Ar² is amino or hydroxy substituted phenyl, X¹ isC₀-C₈-alkyl-X^(1a)—C₀-C₈-alkyl, wherein X^(1a) is —CH₂—, —O—, —S—, —NH—,—C(O)—, then Cy² is not optionally substituted naphthyl or di- or-tetrahydronaphthalene.

In another preferred embodiment of the compounds according to paragraph[0057], when Ay² is o-phenol, Ar² is substituted phenyl, X¹ is —O—, —S—,—CH₂—, —O—CH₂—, —S—CH₂—, or —C(O)—, and R⁵ and R⁶ are H, then Cy² is notoptionally substituted naphthyl.

In another preferred embodiment of the compounds according to paragraph[0057], when Ay² is o-anilinyl, q is O, Ar² is unsubstituted phenyl, X¹is —CH₂—, then Cy² is not substituted6-hydroimidazolo[5,4-d]pyridazin-7-one-1-yl or substituted6-hydroimidazolo[5,4-d]pyridazine-7-thione-1-yl.

Preferably in the compounds according to paragraph [0057], Ay² is phenylor thienyl, each substituted with —OH or —NH₂.

More preferably in the compounds according to paragraph [0057], Ay² isoptionally amino- or hydroxy-substituted phenyl or thienyl, wherein theamino or hydroxy substituent is preferably ortho to the nitrogen towhich Ay² is attached.

More preferably in the compounds according to paragraph [0057], Ay² isortho aniline, ortho phenol, 3-amino-2-thienyl, or 3-hydroxy-2-thienyl,and tautomers thereof.

In a another embodiment, the novel histone deacetylase inhibitors of theinvention are those according to paragraph [0057] wherein

-   -   q is 1;    -   M¹, at each occurrence, is selected from the group consisting of        —N(R⁷)—, —S—, —C(O)—NH—, and —O—C(O)—NH—, where R⁷ is selected        from the group consisting of hydrogen, alkyl, aryl, aralkyl, and        acyl; and    -   Ay² is anilinyl, which optionally is substituted.

In some preferred embodiments of the compounds according to paragraph[0067], the —NH₂ group of Ay² is in an ortho position with respect tothe nitrogen atom to which Ay² is attached. In some embodiments, R⁵ andR⁶ are independently selected from the group consisting of hydrogen andC₁-C₄ alkyl. In some preferred embodiments, R⁵ and R⁶ are hydrogen.

In some embodiments of the compounds according to paragraph [0067], Ar²has the formula

wherein G, at each occurrence, is independently N or C, and C optionallyis substituted. In some preferred embodiments, Ar² has the formula

In some preferred embodiments of the compounds according to paragraph[0069], Ar² is selected from the group consisting of phenylene,pyridylene, pyrimidylene, and quinolylene.

In some embodiments of the compounds according to paragraph [0067], X¹is a chemical bond. In some embodiments, X¹ is L²-M²-L², and M² isselected from the group consisting of —NH—, —N(CH₃)—, —S—, —C(O)—N(H)—,and —O—C(O)—N(H)—. In some embodiments, X¹ is L²-M²-L², where at leastone occurrence of L² is a chemical bond. In other embodiments, X¹ isL²-M²-L², where at least one occurrence of L² is alkylene, preferablymethylene. In still other embodiments, X¹ is L²-M²-L², where at leastone occurrence of L² is alkenylene. In some embodiments, X¹ is M¹-L²-M¹and M¹ is selected from the group consisting of —NH—, —N(CH₃)—, —S—, and—C(O)—N(H)—.

In some embodiments of the compounds according to paragraph [0067], Cy²is aryl or heteroaryl, e.g., phenyl, pyridyl, imidazolyl, or quinolyl,each of which optionally is substituted. In some embodiments, Cy² isheterocyclyl, e.g.,

each of which optionally is substituted and optionally is fused to oneor more aryl rings. In some embodiments, Cy² has from one and threesubstituents independently selected from the group consisting of alkyl,alkoxy, amino, nitro, halo, haloalkyl, and haloalkoxy. Examples ofpreferred substituents include methyl, methoxy, fluoro, trifluoromethyl,trifluoromethoxy, nitro, amino, aminomethyl, and hydroxymethyl.

In a preferred embodiment of the compounds of paragraph [0057], theinvention comprises compounds of structural formula (2a):

and pharmaceutically acceptable salts thereof, wherein

-   -   Ar^(a) is phenyl or thienyl;    -   R⁶ is H, or C₁-C₆-alkyl (preferably —CH₃);    -   Y and Z are independently —CH═ or —N═;    -   W is halo, (V′-L⁴)_(t)-V-L³-;        -   L³ is a direct bond, —C₁-C₆-hydrocarbyl,            —(C₁-C₃-hydrocarbyl)_(m1)-X′—(C₁-C₃-hydrocarbyl)_(m2),            —NH—(C₀-C₃-hydrocarbyl), (C₁-C₃-hydrocarbyl)-NH—, or            —NH—(C₁-C₃-hydrocarbyl)-NH—;            -   m1 and m2 are independently 0 or 1;            -   X′ is —N(R²¹)—, —C(O)N(R²¹)—, N(R²¹)C(O)—, —O—, or —S—;                -   R²¹ is —H, V″—(C₁-C₆-hydrocarbyl)_(c);        -   L⁴ is (C₁-C₆-hydrocarbyl)_(a)-M-(C₁-C₆-hydrocarbyl)_(b);            -   a and b are independently 0 or 1;            -   M is —NH—, —NHC(O)—, —C(O)NH—, —C(O)—, —SO₂—, —NHSO₂—,                or —SO₂NH—        -   V, V′, and V″ are independently selected from cycloalkyl,            heterocyclyl, aryl, and heteroaryl;        -   t is 0 or 1;    -   or W, the annular C to which it is bound, and Y together form a        monocyclic cycloalkyl, heterocyclyl, aryl, or heteroaryl; and    -   wherein the        and Ar^(a) rings are optionally further substituted with from 1        to 3 substituents independently selected from methyl, hydroxy,        methoxy, halo, and amino.

In a preferred embodiment of the compound according to paragraph [0073]:

-   -   Y and Z are —CH═ and R⁶ is H;    -   W is V-L³;        -   L³ is —NH—CH— or —CH—NH—;        -   V is phenyl optionally substituted with from 1 to 3 moieties            independently selected from halo, hydroxy,            C₁-C₆-hydrocarbyl, C₁-C₆-hydrocarbyl-oxy or -thio            (particularly methoxy or methylthio), wherein each of the            hydrocarbyl moieties are optionally substituted with one or            more moieties independently selected from halo, nitroso,            amino, sulfonamido, and cyano; and    -   Ar^(a) is phenyl and the amino moieties to which it is bound are        ortho to each other.

In some preferred embodiments of the compound according to paragraph[0073], V is an optionally substituted ring moiety selected from:

In another preferred embodiment of the compounds according to paragraph[0073], W is selected from:

Br—,

and

In another preferred embodiment of the compounds according to paragraph[0073], the

and Ar^(a) rings are not further substituted.

In a particularly preferred embodiment of the compounds according toparagraph [0073], the compounds of the invention are selected from thefollowing, in which, unless expressly displayed otherwise, Ar^(a) isphenyl (and, preferably, the amide nitrogen and the amino nitrogen boundto Ar^(a) are ortho to each other):

Cpd W Y Z R⁶ 481

CH CH H 484

492

CH CH H 493

CH CH H 494

CH CH H 495

CH CH H 496

CH CH H 497

CH CH H 498

CH CH H 499

CH CH H 500

CH CH H 501

CH CH H 502

CH CH H 503

CH CH H 504

CH CH H 505

CH CH H 506

CH CH H 507

CH CH H 508

CH CH H 509

CH CH H 510

CH CH H 511

CH CH H 512

CH CH H 516 Br— CH CH CH₃ 517

CH CH CH₃ 518

CH CH CH₃ 519

CH CH H 520

CH CH H 521

N CH H 522

N CH H 523

CH CH H 524

N CH H 525

N CH H 526

CH CH H 527

CH CH H 528

CH CH H 529

CH CH H 530

CH CH H 531

CH CH H 532

CH CH H 533

CH CH H 534

CH CH H 535

CH CH H 536

CH CH H 537

CH CH H 538

CH CH H 539

CH CH H 540

CH CH H 541

CH CH H 542

CH CH H 543

CH CH H 544

CH CH H 545

CH CH H 546

CH CH H 547

CH CH H 548

CH CH H 549

CH CH H 550

CH CH H 551

CH CH H 552

CH CH H 553

CH CH H 554

CH CH H 555

CH CH H 556

CH CH H 557

CH CH H 558

CH CH H 559

CH CH H 560

561

562

CH CH H 563

CH CH H 564

565

CH CH H 566

CH CH H 567

568

569

CH N H 570

In a preferred embodiment of the compounds according to paragraph[0057], the invention comprises compounds of the formula (2b):

and pharmaceutically acceptable salts thereof, wherein

-   -   Ay² is phenyl or thienyl, each substituted at the ortho position        with —NH₂ or —OH and each further optionally substituted with        one to three substituents independently selected from —NH₂, —OH,        and halo;    -   q is 0 or 1;    -   X¹ is selected from —CH₂—, —NH—CH₂—, and —S—CH₂—;    -   Cy² is monocyclic or fused bicyclic aryl or heteroaryl        optionally substituted with one to three substituents selected        from CH₃—, CH₃O—, phenyl optionally substituted with one to        three CH₃O—, morphylinyl, morphylinyl-C₁-C₃-alkoxy, cyano, and        CH₃C(O)NH—;    -   provided that when Cy² is naphthyl, X¹ is —CH₂—, and q is 0 or        1, Ay² is not o-hydroxyphenyl.

Preferably in the compounds according to paragraph [0079], Ay² isselected from:

Preferably in the compounds according to paragraph [0079], Cy² isphenyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzothiazolyl, thienyl,tetrahydroquinozolinyl, or 1,3-dihydroquinazoline-2,4-dione, eachoptionally substituted with one to three CH₃O—. More preferably, Cy² isphenyl substituted with one to three CH₃O—.

In a third embodiment, the novel inhibitors of histone deacetylase arerepresented by formula (3):

and pharmaceutical salts thereof, wherein

-   -   Ar³ is arylene or heteroarylene, either of which optionally is        substituted;    -   Cy³ is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of        which optionally is substituted, and each of which optionally is        fused to one or more aryl or heteroaryl rings, or to one or more        saturated or partially unsaturated cycloalkyl or heterocyclic        rings, each of which rings optionally is substituted;    -   provided that when Cy³ is a cyclic moiety having —C(O)—, —C(S)—,        —S(O)—, or —S(O)₂— in the ring, then Cy³ is not additionally        substituted with a group comprising an aryl or heteroaryl ring;        and    -   X² is selected from the group consisting of a chemical bond, L³,        W¹-L³, L³-W¹, W¹-L³-W¹, and L³-W¹-L³, wherein        -   W¹, at each occurrence, is S, O, or N(R⁹), where R⁹ is            selected from the group consisting of hydrogen, alkyl, aryl,            and aralkyl; and        -   L³ is C₁-C₄ alkylene, C₂-C₄ alkenylene, or C₂-C₄ alkynylene;    -   provided that X² does not comprise a —C(O)—, —C(S)—, —S(O)—, or        —S(O)₂— group; and further provided that when Cy³ is pyridine,        then X² is L³, W¹-L³, or L³-W¹.

Preferably, Ar³ has the structure:

wherein Q, at each occurrence, is independently N or C, and C optionallyis substituted.

Preferably in the compounds according to paragraph [0082], X² isselected from the group consisting of L³, W¹-L³, L³-W¹, W¹-L³-W¹, andL³-W¹-L³.

Preferably in the compounds according to paragraph [0082], when X² is achemical bond, then Ar³ is not

and Cy³ is not the radical of a substituted or unsubstituted diazepineor benzofuran.

In some embodiments of the compounds according to paragraph [0082], Q ateach occurrence is C(R⁸), where R⁸ is selected from the group consistingof hydrogen, alkyl, aryl, aralkyl, alkoxy, amino, nitro, halo,haloalkyl, and haloalkoxy. In some other embodiments, from one to aboutthree variables Q are nitrogen. In some preferred embodiments, Ar³ isselected from the group consisting of phenylene, pyridylene,thiazolylene, and quinolylene.

In some embodiments of the compounds according to paragraph [0082], X²is a chemical bond. In other embodiments, X² is a non-cyclichydrocarbyl. In some such embodiments, X² is alkylene, preferablymethylene or ethylene. In other such embodiments, X² is alkenylene oralkynylene. In still other such embodiments, one carbon in thehydrocaryl chain is replaced with —NH— or —S—. In some preferredembodiments, X² is W¹-L³-W¹ and W¹ is —NH— or —N(CH₃)—.

In some embodiments of the compounds according to paragraph [0082], Cy³is cycloalkyl, preferably cyclohexyl. In other embodiments, Cy³ is arylor heteroaryl, e.g., phenyl, pyridyl, pyrimidyl, imidazolyl, thiazolyl,oxadiazolyl, quinolyl, or fluorenyl, each of which optionally issubstituted and optionally is fused to one or more aryl rings. In someembodiments, the cyclic moiety of Cy³ is fused to a benzene ring. Insome embodiments, Cy³ has from one to three substituents independentlyselected from the group consisting of alkyl, alkoxy, aryl, aralkyl,amino, halo, haloalkyl, and hydroxyalkyl. Examples of preferredsubstituents include methyl, methoxy, fluoro, trifluoromethyl, amino,nitro, aminomethyl, hydroxymethyl, and phenyl. Some other preferredsubstituents have the formula —K¹—N(H)(R¹⁰), wherein

-   -   K¹ is a chemical bond or C₁-C₄ alkylene;    -   R¹⁰ is selected from the group consisting of Z′ and -Ak²-Z′,        wherein        -   Ak² is C₁-C₄ alkylene; and        -   Z′ is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of            which optionally is substituted, and each of which            optionally is fused to one or more aryl or heteroaryl rings,            or to one or more saturated or partially unsaturated            cycloalkyl or heterocyclic rings.

Examples of such preferred substituents according to paragraph [0088]include

In some embodiments of the compounds according to paragraph [0082], Cy³is heterocyclyl, e.g.,

each of which optionally is substituted and optionally is fused to oneor more aryl rings. In some embodiments, the heterocycle of Cy³ is fusedto a benzene ring.

Preferably in the compounds of paragraph [0082], when Ar⁴ isquinoxalinylene, then X³ is not —CH(OH)—.

In another preferred embodiment, Ar³ is

wherein X is —CH₂—, —NH—, O, or S. Preferably Ar³ is

and X is S or O.

In a preferred embodiment, the novel histone deacetylase inhibitors ofthe invention are those according to paragraph [0057] wherein

-   -   Ay² is ortho-anilinyl;    -   q is O; and    -   X¹ is M¹-L²-M¹ or L²-M²-L².

In a preferred embodiment of the compounds according to paragraph[0093], Ar² is aryl or heteroaryl; and Cy²-X¹— is collectively selectedfrom the group consisting of

-   -   a) A₁-L₁-B¹—, wherein A₁ is an optionally substituted aryl,        optionally substituted heteroaryl or optionally substituted        heterocyclyl; wherein L₁ is —(CH₂)₀₋₁NH(CH₂)₀₋₁—, —NHC(O)—, or        —NHCH₂—; and wherein B₁ is phenyl or a covalent bond;    -   b) A₂-L₂-B₂—, wherein A₂ is CH₃(C═CH₂)—, optionally substituted        cycloalkyl, optionally substituted alkyl, or optionally        substituted aryl; wherein L₂ is —C≡C—; and wherein B₂ is a        covalent bond;    -   c) A₃-L₃-B₃—, wherein A₃ is an optionally substituted aryl,        optionally substituted heteroaryl or optionally substituted        heterocyclyl; wherein L₃ is a covalent bond; and wherein B₃ is        —CH₂NH—;    -   d) A₄-L₄-B₄—, wherein A₄ is an optionally substituted aryl;        wherein L₄ is —NHCH₂—; and wherein B₄ is a thienyl group;    -   e) A₅-L₅-B₅—, wherein A₅ is an optionally substituted heteroaryl        or optionally substituted heterocyclyl; wherein L₅ is a covalent        bond; and wherein B₅ is —SCH₂—;    -   f) morpholinyl-CH₂—    -   g) optionally substituted aryl;    -   h) A₆-L₆-B₆—, wherein A₆ is an optionally substituted aryl,        optionally substituted heteroaryl or optionally substituted        heterocyclyl; wherein L₆ is a covalent bond; and wherein B₆ is        —NHCH₂—;    -   i) A₇-L₇-B₇—, wherein A₇ is an optionally substituted heteroaryl        or optionally substituted heterocyclyl; wherein L₇ is a covalent        bond; and wherein B₇ is —CH₂—;    -   j) aptionally substituted heteroaryl or optionally substituted        heterocyclyl;    -   k) A₈L₈-B₈—, wherein A₈ is optionally substituted phenyl;        wherein L₈ is a covalent bond; and wherein B₈ is —O—;    -   l) A₉-L₉-B₉—, wherein A₉ is an optionally substituted aryl;        wherein L₉ is a covalent bond; and wherein B₉ is a furan group;    -   m) A₁₀-L₁₀-B₁₀—, wherein A₁₀ is an optionally substituted        heteroaryl or optionally substituted heterocyclyl; wherein L₁₀        is —CH(CH₂CH₃)—; and wherein B₁₀ is —NHCH₂—;    -   n) A₁₁-L₁₁-B₁₁—, wherein A₁₁ is an optionally substituted        heteroaryl or optionally substituted heterocyclyl; wherein L₁₁        is a covalent bond; and wherein B₁₁ is —OCH₂—;    -   o) A₁₂-L₁₂-B₁₂—, wherein A₁₂ is an optionally substituted aryl,        optionally substituted heteroaryl or optionally substituted        heterocyclyl; wherein L₁₂ is —NHC(O)—; and wherein B₁₂ is        —N(optionally substituted aryl)CH₂—;    -   p) A₁₃-L₁₃-B₁₃—, wherein A₁₂ is an optionally substituted aryl,        optionally substituted heteroaryl or optionally substituted        heterocyclyl; wherein L₁₃ is a covalent bond; and wherein B₁₃ is        —NHC(O)—;    -   q) A₁₄-L₁₄-B₁₄—, wherein A₁₄ is an optionally substituted aryl,        optionally substituted heteroaryl or optionally substituted        heterocyclyl; wherein L₁₄ is —NHC(O)(optionally substituted        heteroaryl); and wherein B₁₄ is —S—S—;    -   r) F₃CC(O)NH—;    -   s) A₁₅-L₁₅-B₁₅—, wherein A₁₅ is an optionally substituted aryl,        optionally substituted heteroaryl or optionally substituted        heterocyclyl; wherein L₁₅ is —(CH₂)₀₋₁NH(optionally substituted        heteroaryl)—; and wherein B₁₅ is —NHCH₂—;    -   t) A₁₆-L₁₆-B₁₆—, wherein A₁₆ is an optionally substituted aryl,        optionally substituted heteroaryl or optionally substituted        heterocyclyl; wherein L₁₆ is a covalent bond; and wherein B₁₆ is        —N(optionally substituted alkyl)CH₂—; and    -   u) A₁₆-L₁₆-B₁₆—, wherein A₁₆ is an optionally substituted aryl,        optionally substituted heteroaryl or optionally substituted        heterocyclyl; wherein L₁₆ is a covalent bond; and wherein B₁₆ is        -(optionally substituted aryl-CH₂)₂—N—.

In another preferred embodiment of the compounds according to paragraph[0093], Cy²-X¹— is collectively selected from the group consisting of

-   -   a) D₁-E₁-F₁—, wherein D₁ is an optionally substituted aryl,        optionally substituted heteroaryl or optionally substituted        heterocyclyl; wherein E₁ is —CH₂— or a covalent bond; and        wherein B₁ is a covalent bond;    -   b) D₂-E₂-F₂—, wherein D₂ is an optionally substituted aryl,        optionally substituted heteroaryl or optionally substituted        heterocyclyl; wherein E₂ is —NH(CH₂)₀₋₂—; and wherein F₂ is a        covalent bond;    -   c) D₃-E₃-F₃—, wherein D₃ is an optionally substituted aryl,        optionally substituted heteroaryl or optionally substituted        heterocyclyl; wherein E₃ is —(CH₂)₀₋₂NH—; and wherein F₃ is a        covalent bond;    -   d) D₄-E₄-F₄—, wherein D₄ is an optionally substituted aryl,        optionally substituted heteroaryl or optionally substituted        heterocyclyl; wherein E₄ is —S(CH₂)₀₋₂—; and wherein F₄ is a        covalent bond;    -   e) D₅-E₅-F₅—, wherein D₅ is an optionally substituted aryl,        optionally substituted heteroaryl or optionally substituted        heterocyclyl; wherein E₅ is —(CH₂)₀₋₂S—; and wherein F₅ is a        covalent bond; and    -   f) D₆-E₆-F6—, wherein D₆ is an optionally substituted aryl,        optionally substituted heteroaryl or optionally substituted        heterocyclyl; wherein E₆ is —NH(CH₂)₀₋₂NH—; and wherein F₆ is a        covalent bond.

In a preferred embodiment, the HDAC inhibitors of the invention comprisecompounds of paragraph [0057] having formula (3b):

and pharmaceutically acceptable salts thereof, wherein Y and Z areindependently N or CH and W is selected from the group consisting of:

and

In a preferred embodiment of the compounds according to paragraph[0096], the compounds comprise those wherein Y, Z and W are as definedbelow:

Cpd W Y Z 164

CH CH 165

N CH 166

CH CH 167

CH N 168

CH N 169

CH CH 170

CH CH 171

N CH 172

CH CH 174

CH N 175

CH N 176

CH N 177

CH CH 178

N CH 179

CH CH 180

CH CH 181

CH CH 182

CH CH and 183

CH CH

In another preferred embodiment of the compounds according to paragraph[0096], the compounds comprise those wherein Y, Z and W are as definedbelow:

Cpd W Y Z 187

CH CH 188

CH CH 189

CH CH 190

CH CH 193

CH CH 194

CH CH 195

CH CH 196

CH CH 320

CH CH 321

CH CH 322

CH CH 323

CH CH 325

CH CH 326

CH CH 327

CH CH 328

CH CH 329

CH CH 330

CH CH 331

CH CH 332

CH CH 333

CH CH 334

CH CH 335

CH CH 336

CH CH 337

CH CH 338

CH CH 339

CH CH 340

CH CH 341

CH CH 342

CH CH 343

CH CH 344

CH CH 345

CH CH 346

CH CH 347

CH CH 348

CH CH 349

CH CH 350

CH CH 351

CH CH 352

CH CH 353

CH CH 354

CH CH 355

CH CH 356

CH CH 357

CH CH 358

CH CH 359

CH CH 360

CH CH 361

CH CH 362

CH CH 363

CH CH 364

CH CH 365

CH CH 366

CH CH 367

CH CH 368

CH CH 369

CH CH 370

CH CH 371

CH CH 372

CH CH 373

CH CH 374

CH CH 375

CH CH 377

CH CH 378

CH CH 379

CH CH 380

CH CH 381

CH CH 382

CH CH 383

CH CH 384

CH CH 385

CH CH 386

CH CH 387

CH CH 388

CH CH 389

CH CH 390

CH CH 391

CH CH 392

CH CH 393

CH CH 394

CH CH 395

CH CH 396

CH CH 397

CH CH 398

CH N 399

CH CH 400

CH CH 401

CH CH 402

CH CH 403

CH CH 404

CH CH 405

CH CH 406

CH CH 407

CH CH 408

CH CH 409

CH CH 410

CH CH 411

CH CH 412

CH CH 413

CH CH 414

CH CH 415

CH CH 416

CH CH 417

CH CH 418

CH CH 419

CH CH 420

CH CH 421

CH CH 422

CH CH 423

CH CH 424b

CH CH 425

CH CH 426

CH CH 427

CH CH 428

CH CH 429

CH CH 430

CH CH 431

CH CH 432

CH CH 433

CH CH 434

CH CH 435

CH CH 436

CH CH 437

CH CH 438

CH CH 439

CH CH 440

CH CH 441

CH CH 442

CH CH 443

CH CH 444

CH CH 445

CH N 446

CH N 447

CH CH 448

CH CH 449

CH CH 450

CH CH 451

CH CH 452

CH CH 453

454

455

CH CH 456

CH CH 457

458

CH CH 459

CH CH 460

CH N 461

CH CH 462

CH CH 463

N CH 464

N CH 465

CH CH 466

CH CH 467

CH CH 468

CH CH

In yet another a preferred embodiment, the novel histone deacetylaseinhibitors of the on are selected from the group consisting of thefollowing and their pharmaceutically able salts:

In another preferred embodiment, the compounds are selected from thoselisted in Tables 2a-b, 3a-d, 4a-c, and 5a-5f.

Synthesis

Compounds of formula (1), wherein Y¹ is —N(R¹)(R²), preferably may beprepared according to the synthetic route depicted in Scheme 1. Thus,trichlorotriazine I reacts with amine II in the presence ofdiisopropylethylamine to produce dichloroaminotriazine III. The amineR¹R²NH is added to dichloroaminotriazine III to producediaminochlorotriazine V. Treatment of V with ammonia or R³R⁴NH intetrahydrofuran (THF) or 1,4 dioxane affords triaminotriazine VI.

Alternatively, dichloroaminotriazine III may be reacted with ammonia gasin 1,4 dioxane to produce diaminochlorotriazine IV. Treatment of IV withR¹R²NH in THF or 1,4 dioxane in a sealed flask then affordstriaminotriazine VI.

Hydrolysis of the ester moiety in VI is effected by treatment with ahydroxide base, such as lithium hydroxide, to afford the correspondingacid VII. Treatment of the acid VII with 1,2-phenylenediamine in thepresence of BOP reagent, triethylamine, and dimethylformamide (DMF)yields the anilinyl amide VII.

Compounds of formula (1), wherein Y¹ is —CH₂—C(O)—N(R¹)(R²), preferablymay be prepared as outlined in Scheme 2. Thus, piperazine IX is treatedwith acetyl chloride and triethylamine to produce amide X. Reaction of Xwith dichloromorpholyltriazine and lithium hexamethyidisiloxane affordscompound XI. The chloride of XI is converted to the anilinyl amide ofXII as described above with respect to Scheme 1: treatment with theamine and diisopropylethylamine; followed by lithium hydroxide; followedby BOP reagent, phenylenediamine, triethylamine, and DMF.

Compounds of formula (2), wherein Ar² is pyridylene and X¹ comprises—N(R⁷)—, compounds of formula (3), wherein Ar³ is pyridylene and X²comprises —N(R⁹)—, and compounds of formula (4), wherein Ar⁴ ispyridylene and X³ comprises —N(R¹¹)—, preferably may be preparedaccording to the procedures illustrated in Scheme 3. Dibromopyridine XIIor XIV is treated with amine RNH₂ to produce aminobromopyridine XV orXVI, respectively. Treatment of XV or XVI with diacetoxypalladium,diphenylphosphinoferrocene, DMF, diisopropylethylamine, andphenylenediamine under carbon monoxide yields anilinyl amide XVII orXVIII, respectively.

Treatment of XV or XVI with tert-butylacrylate, diisopropylethylamine,dibenzylacetone palladium, and tri-o-tolylphosphine (POT) in DMF undernitrogen affords compounds XIX and XX, respectively. The ester moiety ofXIX or XX is hydrolyzed to produce the corresponding acid moiety in XXIor XXII, respectively, by reaction with trifluoroacetic acid indichloromethane. Treatment of the acid XXI or XXII withphenylenediamine, BOP, and triethylamine affords the anilinyl amideXXIII or XXIV, respectively.

Compounds of formula (2), wherein X¹ comprises —O—C(O)—NH—, preferablymay be prepared according to the synthetic route depicted in Scheme 4.Thus, carbinol XXV is added to bromobenzylamine XXVI withcarbonyldiimidazole (CDI), triethylamine, and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in DMF to produce compoundXXVII. The remaining synthetic steps in the production of anilinyl amideXXVIII are as described above for Scheme 3.

Compounds of formula (2), wherein X¹ comprises —N(R⁷)—, preferably maybe prepared as outlined in Scheme 5. Amine XXIX is reacted withp-bromobenzylbromide in the presence of potassium carbonate in DMF toproduce bromobenzylamine XXX. Treatment of XXX with nitroacrylanilide,dibenzylacetone palladium, POT, and diisopropylethylamine in DMF affordsnitroanilide XXXI. Nitroanilide XXXI is converted to the correspondinganilinyl amide XXXII by treatment with stannous chloride in methanol andwater.

Treatment of amine XXXI in formic acid with paraformaldehyde providesmethylamine XXXIII. The nitroanilide moiety in XXXIII is then convertedto the corresponding anilinyl amide moiety in XXXIV by treatment withstannous chloride in methanol and water.

Alternatively, compounds of formula (2), wherein X¹ comprises —N(R⁷)—,may be prepared according to the synthetic route depicted in Scheme 6.Carboxylic acid XXXV in methanol is treated with hydrochloric acid toproduce ester XXXVI. Conversion of the primary amine moiety in XXXVI tothe secondary amine moiety in XXXVI is effected by treatment with acatalyst such as triethylamine, methoxybenzylchloride, sodium iodide,and potassium carbonate in DMF at 60° C. Ester XXXVI is converted toanilinyl amide XXXVII by treatment with sodium hydroxide, THF, andmethanol, followed by BOP, triethylamine, and phenylenediamine in DMF,as described above for Scheme 3.

Compounds of formula (2), wherein X¹ comprises

or —C(O)—NH—, preferably may be prepared according to the proceduresillustrated in Scheme 7. Addition of amine 68 to haloaryl compoundXXXVIII or XXXIX and potassium carbonate in DMF provides arylamine XL orXLI, respectively. Anilinyl amide XLII or XLIII is then prepared usingprocedures analogous to those set forth in Schemes 3-6 above.

Compounds such as XLVII and XLIX preferably may be prepared as outlinedin Scheme 8. Dibromopyridine is combined with diaminoethane to produceamine XLIV. Treatment of amine XLIV with isatoic anhydride LV inmethanol and water, followed by refluxing in formic acid affordscompound XLVI. Treatment of amine XLIV with the reaction products ofbenzylaminodiacetic acid and acetic anhydride provides compound XLVIII.Bromopyridylamines XLVI and XLVIII are then converted to thecorresponding diene anilinylamides XLVII and XLIX, respectively, byprocedures analogous to those set forth in Schemes 3-7 above.

Compounds such as LIV preferably may be prepared according to thesynthetic route depicted in Scheme 9. Trichlorotriazine is treated withaminoindan and diisopropylethylamine to produce dichloroaminotriazine L.Treatment with bromobenzylamine and diisopropylethylamine affordsdiaminochlorotriazine LI. Addition of ammonia gas and dioxane providestriaminotriazine LII. Treatment with protected acrylanilide,triethylamine, POT, and dibenzylacetone palladium then yields dieneanilinylamide LII, which is deprotected with trifluoroacetic acid toprovide the final product LIV.

Compounds of formula (2), wherein Ar² is quinolylene and X¹ comprises—N(R⁷)—, compounds of formula (3), wherein Ar³ is quinolylene and X²comprises —N(R⁹)—, and compounds of formula (4), wherein Ar⁴ isquinolylene and X³ comprises —N(R¹¹)—, preferably may be preparedaccording to the procedures illustrated in Scheme 10. DihydroxyquinolineLV with dimethylaminopyridine (DMAP) in pyridine is treated withtrifluoromethanesulfonic anhydride to providebis(trifluoromethanesulfonyloxy)-quinoline LVI. Treatment of LVI withp-methoxybenzylamine affords aminoquinoline LVII. Anilinyl amides LVIIIand LIX are then prepared using procedures analogous to those describedfor Schemes 1-9 above.

Compounds of formula (3), wherein X² comprises a sulfur atom, andcompounds of formula (4), wherein X³ comprises a sulfur atom, preferablymay be prepared as outlined in Scheme 11. Bromide LX is converted todiaryl ester LXI using procedures analogous to those described forScheme 6 above. Synthetic methods similar to those set forth in Scheme 1above are then used to convert ester LXI to the corresponding acid LXIV.Alternatively, ester LXI may be treated with chloroethylmorphonline,sodium iodide, potassium carbonate, triethylamine, andtetrabutylammonium iodide (TBAI) in DMF to produce ester LXIII, which isthen converted to acid LXIV as in Scheme 1. Conversion of the acid LXIVto the anilinyl amide LXV is effected by procedures analogous to thoseset forth in Scheme 1 above.

Alternatively, compounds of formula (3), wherein X² comprises a sulfuratom, and compounds of formula (4), wherein X³ comprises a sulfur atom,may be prepared according to the procedures illustrated in Scheme 12.Sulfanyl anilinylamide LXVIII is prepared using procedures analogous tothose set forth in Schemes 3 and 5 above.

Compounds of formula (3), wherein X² comprises —N(R⁹)—, and compounds offormula (4), wherein X³ comprises —N(R¹¹)—, preferably may be preparedaccording to the synthetic route depicted in Scheme 13. Amino anilinylamide LXXI is prepared according to synthetic steps similar to thosedescribed for Schemes 1 and 6 above.

Compounds of formula (3), wherein X² comprises a sulfur atom, andcompounds of formula (4), wherein X³ comprises a sulfur atom, preferablymay be prepared as outlined in Scheme 14. Phenylenediamine is reactedwith di-tert-butyldicarbonate, followed by iodobenzoic acid,dimethylaminopropylethylcarbodiimide, hydroxybenzotriazole, andtriethylamine to provide protected anilinyl amide LXXII. The iodidemoiety of LXXII is converted to the methyl ester moiety of LXXIII usingprocedures analogous to those set forth for Scheme 3 above. The methylester moiety of LXXIII is converted to the hydroxyl moiety of LXXIV bytreatment with a reducing agent such as diisobutylaluminum hydride(DIBAL-H). Addition of the heterocyclylsulfhydryl compound Het-SH withtriphenylphosphine and diethylazodicarboxylate converts the hydroxylmoiety of LXXIV to the sulfanyl moiety of LXXV. LXXV is deprotected withtrifluoroacetic acid to afford the sulfanyl anilinyl amide LXXVI.

Compounds of formula (3), wherein X² is a chemical bond, preferably maybe prepared according to the synthetic route depicted in Scheme 15.Thus, chloroarylanilinylamide LXXVII is treated with aryl boronic acid,benzene, ethanol, aqueous sodium carbonate, and triphenylphosphinepalladium to afford the diarylanilinylamide LXXVIII.

Compounds such as LXXXI preferably may be prepared according to theprocedues illustrated in Scheme 16. Thus, benzene-1,2-carbaldehyde LXXIXin acetic acid is treated with p-aminomethylbenzoic acid to produce thebenzoic acid LXXX. The acid LXXX is converted to the correspondinganilinylamide LXXXI by treatment with hydroxybenzotriazole,ethylenedichloride, and phenylenediamine.

Compounds such as LXXXVI and LXXXIX preferably may be prepared accordingto the procedures illustrated in Scheme 18. Phthalic anhydride LXXXV andp-aminomethylbenzoic acid are combined in acetic acid to produce anintermediate carboxylic acid, which is converted to the anilinylamideLXXXVI using procedures analogous to those set forth in Schemes 15 and16 above.

The addition of 4-(2-aminoethyl)phenol to phthalic anhydride LXXXV inacetic acid affords the hydroxyl compound LXXXVII. The hydroxyl group ofLXXXVII is converted to the triflate group of LXXXVIII by treatment withsodium hydride, THF, DMF, and phenylaminoditriflate. Treatment ofLXXXVIII according to procedures analogous to those described for Scheme3 above affords the anilinylamide LXXXIX.

Compounds such as XCI-XCVI preferably may be prepared according to thesynthetic route depicted in Scheme 19. Treatment of isatoic anhydride XCwith p-aminomethylbenzoic acid in water and triethylamine, followed byformic acid affords an intermediate carboxylic acid, which is convertedto anilinylamide XCI using procedures analogous to those described forScheme 16 above.

Alternatively, treatment of isatoic acid XC with p-aminomethylbenzoicacid in water and triethylamine, follwed by hydrochloric acid and sodiumnitrite affords an intermediate carboxylic acid, which is converted toanilinylamide XCII using procedures analogous to those described forScheme 16 above.

Alternatively, treatment of isatoic acid XC with p-aminomethylbenzoicacid in water and triethylamine affords benzoic acid XCIII. Treatment ofXCIII with sodium hydroxide, dioxane, methylchloroformate, and methanolaffords an intermediate quinazolinedione carboxylic acid, the acidmoiety of which is then converted to the anilinylamide moiety of XCIVusing procedures analogous to those described for Scheme 16 above.Alternatively, the intermediate quanzolinedione carboxylic acid in DMFis treated with potassium carbonate and methyl iodide to produce anintermediate benzoic acid methyl ester, which is converted to anintermediate benzoic acid by treatment with sodium hydroxide, methanol,and water. The benzoic acid is then converted to the correspondinganilinylamide XCV using procedures analogous to those described forScheme 16 above.

Alternatively, treatment of XCIII with acetic anhydride followed byacetic acid produces an intermediate carboxylic acid, which is convertedto anilinylamide XCVI using procedures analogous to those described forScheme 16 above.

Compounds such as C preferably may be prepared as outlined in Scheme 20.Alkylamine XCVII is treated with thiocarbonyl diimidazole indichloromethane, follwed by ammonium hydroxide to afford thioureaXCVIII. Treatment of thiourea XCVIII with methylmethoxyacrylate indioxane and N-bromosuccinimide produces thiazole ester IC. The ester ICis converted to the corresponding anilinylamine C using proceduresanalogous to those set forth in Scheme 1 above.

Compounds of formula (3), wherein X² is a chemical bond and Cy³ has anamino substituent preferably may be prepared according to the syntheticroute depicted in Scheme 21. Thus, protected iodoarylanilinylamide CI istreated according to procedures analogous to those described for Scheme15 above afford the diarylanilinylamide CII. The aldehyde moiety in CIIis converted to the corresponding secondary amine moiety by treatmentwith the primary amine and sodium triacetoxyborohydride followed byglacial acetic acid. The resultant compound is deprotected to yield CIIIusing procedures analogous to those set forth in Scheme 3 above.

Compounds of formula (3), wherein X² comprises an alkynylene moiety, andcompounds of formula (4), wherein X³ comprises an alkynylene moiety,preferably may be prepared as outlined in Scheme 22. Treatment ofprotected iodoarylanilinylamide CI with triphenylphosphine palladiumchloride, cuprous iodide, and 1-ethynylcyclohexylamine affords thealkynylarylanilinylamide CIV. The primary amine moiety in CIV isconverted to the corresponding secondary amine and the aniline moiety isdeprotected to afford CV using procedures analogous to those describedfor Scheme 21 above.

Compounds such as CVIII preferably may be prepared according to thesynthetic route depicted in Scheme 24. Dichloroaminotriazine CVI istreated with methyl-4aminobenzoate in the presence ofdiisopropylethylamine to produce diaminotriazine CVII. Addition ofammonia gas and dioxane, followed by a saponification and a peptidecoupling using the same procedures analogous to those described forScheme 1 above.

Compounds such as CX preferably may be prepared according to thesynthetic route depicted in Scheme 30. The Grignard reaction oftrichloroaminotriazine with various alkyl magnesium bromide, followed bya treatment with methyl-4-aminobenzoate in the presence ofdiisopropylethylamine yields alkylaminotriazine CIX. Synthetic methodssimilar to those set forth in Scheme 1 above are then used to convertester CIX to the corresponding anilinyl amide CX.

Amination of dichlorotriazine proceeded using the usual conditiondescribed in Scheme 1 to afford CXI. Stille coupling using vinylstannane provides CXII. Treatment with protected iodoanilide,triethylamine, POT and dibenzylacetone palladium then yieldsanilinylamide, which is deprotected with trifluoroacetic acid to providethe alkene CXIII. Hydrogenation of the alkene affords the final compoundCXIV.

Compounds such as CXVIII preferably may be prepared according to thesynthetic route depicted in Scheme 33. Treatment ofmethoxyaminobenzothiazole with tribromide boron affords thecorresponding acid CXV. Mitsunobu reaction using hydroxyethyl morpholinein the presence of diethylazodicarboxylate and triphenylphosphine yieldsthe amine CXVI. Reductive amination with methyl-4-formylbenzoate usingphenylsilane and tin catalyst yields to the ester CXVII. Saponificationfollowed by the usual peptide coupling analogous to those describe forScheme 1 above provides the desired anilide CXVIII.

Treatment 4-methylcyanobenzoic acid with hydrogen sulfide affords CXIX,which is subjected to cyclization in the presence of 1,3-dichloroacetoneto yield CXX. Treatment with morpholine followed by a peptide couplingusing the standard condition produces CXXI.

Compounds such as CXXIII and CXXVII preferably may be prepared accordingto the synthetic scheme 49. Consecutive treatment of acetyl acetone withmethyl bromomethylbenzoate in the presence of NaOMe and phenyl hydrazinefollowed by saponification, afforded the intermediate acid CXXII. Thismaterial was coupled with 1,2-diaminobenzene in a standard fashion toafford CXXIII.

Consecutive treatment of acetyl acetone with methyl bromomethylbenzoatein the presence of NaOMe and a 1:1 mixture AcOH—HCl (conc.) afforded theintermediate acid CXXIV. This keto-acid reacting with sulfur andmalonodinitrile in the presence of a base, produced the thiophene CXXV,which was converted into the desired CXXVII using standard procedures.

Compounds such as CXXX preferably may be prepared according to thesynthetic scheme 50. Treatment of 4-cyanomethylbenzoic acid withhydroxylamine produced the amidoxime CXXVIII, which upon treatment withacetic anhydride was converted into the oxadiazole CXXIX. The latter wascoupled with 1,2-diaminobenzene in a standard fashion to afford CXXX.

Compounds such as CXXXIII preferably may be prepared according to thesynthetic route depicted in Scheme 57. Treatment of 4-formylbenzoic acidwith thionyl chloride afford the acyl chloride which is coupled withprotected anilide to produce CXXXI. Reductive amination withdimethoxyaniline using phenylsilane and tin catalyst yields to theprotected anilide CXXXII. Treatment with isocyanate followed bydeprotection with trifluoroacetic acid provides the ureidoanilideCXXXIII.

Pharmaceutical Compositions

In a second aspect, the invention provides pharmaceutical compositionscomprising an inhibitor of histone deacetylase according to theinvention and a pharmaceutically acceptable carrier, excipient, ordiluent. Compounds of the invention may be formulated by any method wellknown in the art and may be prepared for administration by any route,including, without limitation, parenteral, oral, sublingual,transdermal, topical, intranasal, intratracheal, or intrarectal. Incertain preferred embodiments, compounds of the invention areadministered intravenously in a hospital setting. In certain otherpreferred embodiments, administration may preferably be by the oralroute.

The characteristics of the carrier will depend on the route ofadministration. As used herein, the term “pharmaceutically acceptable”means a non-toxic material that is compatible with a biological systemsuch as a cell, cell culture, tissue, or organism, and that does notinterfere with the effectiveness of the biological activity of theactive ingredient(s). Thus, compositions according to the invention maycontain, in addition to the inhibitor, diluents, fillers, salts,buffers, stabilizers, solubilizers, and other materials well known inthe art. The preparation of pharmaceutically acceptable formulations isdescribed in, e.g., Remington's Pharmaceutical Sciences, 18th Edition,ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

As used herein, the term pharmaceutically acceptable salts refers tosalts that retain the desired biological activity of theabove-identified compounds and exhibit minimal or no undesiredtoxicological effects. Examples of such salts include, but are notlimited to acid addition salts formed with inorganic acids (for example,hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid, and the like), and salts formed with organic acids such asacetic acid, oxalic acid, tartaric acid, succinic acid, malic acid,ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid,polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid,and polygalacturonic acid. The compounds can also be administered aspharmaceutically acceptable quaternary salts known by those skilled inthe art, which specifically include the quaternary ammonium salt of theformula —NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is acounterion, including chloride, bromide, iodide, —O-alkyl,toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate(such as benzoate, succinate, acetate, glycolate, maleate, malate,citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate,benzyloate, and diphenylacetate).

The active compound is included in the pharmaceutically acceptablecarrier or diluent in an amount sufficient to deliver to a patient atherapeutically effective amount without causing serious toxic effectsin the patient treated. A preferred dose of the active compound for allof the above-mentioned conditions is in the range from about 0.01 to 300mg/kg, preferably 0.1 to 100 mg/kg per day, more generally 0.5 to about25 mg per kilogram body weight of the recipient per day. A typicaltopical dosage will range from 0.01-3% wt/wt in a suitable carrier. Theeffective dosage range of the pharmaceutically acceptable derivativescan be calculated based on the weight of the parent compound to bedelivered. If the derivative exhibits activity in itself, the effectivedosage can be estimated as above using the weight of the derivative, orby other means known to those skilled in the art.

Inhibition of Histone Deacetylase

In a third aspect, the invention provides a method of inhibiting histonedeacetylase in a cell, comprising contacting a cell in which inhibitionof histone deacetylase is desired with an inhibitor of histonedeacetylase according to the invention. Because compounds of theinvention inhibit histone deacetylase, they are useful research toolsfor in vitro study of the role of histone deacetylase in biologicalprocesses. In addition, the compounds of the invention selectivelyinhibit certain isoforms of HDAC.

Measurement of the enzymatic activity of a histone deacetylase can beachieved using known methodologies. For example, Yoshida et al., J.Biol. Chem., 265: 17174-17179 (1990), describes the assessment ofhistone deacetylase enzymatic activity by the detection of acetylatedhistones in trichostatin A treated cells. Taunton et al., Science, 272:408-411 (1996), similarly describes methods to measure histonedeacetylase enzymatic activity using endogenous and recombinant HDAC-1.

In some preferred embodiments, the histone deacetylase inhibitoririteracts with and reduces the activity of all histone deacetylases inthe cell. In some other preferred embodiments according to this aspectof the invention, the histone deacetylase inhibitor interacts with andreduces the activity of fewer than all histone deacetylases in the cell.In certain preferred embodiments, the inhibitor interacts with andreduces the activity of one histone deacetylase (e.g., HDAC-1), but doesnot interact with or reduce the activities of other histone deacetylases(e.g., HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, and HDAC-8). Asdiscussed below, certain particularly preferred histone deacetylaseinhibitors are those that interact with, and reduce the enzymaticactivity of, a histone deacetylase that is involved in tumorigenesis.Certain other preferred histone deacetylase inhibitors interact with andreduce the enzymatic activity of a fungal histone deacetylase.

Preferably, the method according to the third aspect of the inventioncauses an inhibition of cell proliferation of the contacted cells. Thephrase “inhibiting cell proliferation” is used to denote an ability ofan inhibitor of histone deacetylase to retard the growth of cellscontacted with the inhibitor as compared to cells not contacted. Anassessment of cell proliferation can be made by counting contacted andnon-contacted cells using a Coulter Cell Counter (Coulter, Miami, Fla.)or a hemacytometer. Where the cells are in a solid growth (e.g., a solidtumor or organ), such an assessment of cell proliferation can be made bymeasuring the growth with calipers and comparing the size of the growthof contacted cells with non-contacted cells.

Preferably, growth of cells contacted with the inhibitor is retarded byat least 50% as compared to growth of non-contacted cells. Morepreferably, cell proliferation is inhibited by 100% (i.e., the contactedcells do not increase in number). Most preferably, the phrase“inhibiting cell proliferation” includes a reduction in the number orsize of contacted cells, as compared to non-contacted cells. Thus, aninhibitor of histone deacetylase according to the invention thatinhibits cell proliferation in a contacted cell may induce the contactedcell to undergo growth retardation, to undergo growth arrest, to undergoprogrammed cell death (i.e., to apoptose), or to undergo necrotic celldeath.

The cell proliferation inhibiting ability of the histone deacetylaseinhibitors according to the invention allows the synchronization of apopulation of asynchronously growing cells. For example, the histonedeacetylase inhibitors of the invention may be used to arrest apopulation of non-neoplastic cells grown in vitro in the G1 or G2 phaseof the cell cycle. Such synchronization allows, for example, theidentification of gene and/or gene products expressed during the G1 orG2 phase of the cell cycle. Such synchronization of cultured cells mayalso be useful for testing the efficacy of a new transfection protocol,where transfection efficiency varies and is dependent upon theparticular cell cycle phase of the cell to be transfected. Use of thehistone deacetylase inhibitors of the invention allows thesynchronization of a population of cells, thereby aiding detection ofenhanced transfection efficiency.

In some preferred embodiments, the contacted cell is a neoplastic cell.The term “neoplastic cell” is used to denote a cell that shows aberrantcell growth. Preferably, the aberrant cell growth of a neoplastic cellis increased cell growth. A neoplastic cell may be a hyperplastic cell,a cell that shows a lack of contact inhibition of growth in vitro, abenign tumor cell that is incapable of metastasis in vivo, or a cancercell that is capable of metastasis in vivo and that may recur afterattempted removal. The term “tumorigenesis” is used to denote theinduction of cell proliferation that leads to the development of aneoplastic growth. In some embodiments, the histone deacetylaseinhibitor induces cell differentiation in the contacted cell. Thus, aneoplastic cell, when contacted with an inhibitor of histone deacetylasemay be induced to differentiate, resulting in the production of anon-neoplastic daughter cell that is phylogenetically more advanced thanthe contacted cell.

In some preferred embodiments, the contacted cell is in an animal. Thus,the invention provides a method for treating a cell proliferativedisease or condition in an animal, comprising administering to an animalin need of such treatment a therapeutically effective amount of ahistone deacetylase inhibitor of the invention. Preferably, the animalis a mammal, more preferably a domesticated mammal. Most preferably, theanimal is a human.

The term “cell proliferative disease or condition” is meant to refer toany condition characterized by aberrant cell growth, preferablyabnormally increased cellular proliferation. Examples of such cellproliferative diseases or conditions include, but are not limited to,cancer, restenosis, and psoriasis. In particularly preferredembodiments, the invention provides a method for inhibiting neoplasticcell proliferation in an animal comprising administering to an animalhaving at least one neoplastic cell present in its body atherapeutically effective amount of a histone deacetylase inhibitor ofthe invention.

It is contemplated that some compounds of the invention have inhibitoryactivity against a histone deacetylase from a protozoal source. Thus,the invention also provides a method for treating or preventing aprotozoal disease or infection, comprising administering to an animal inneed of such treatment a therapeutically effective amount of a histonedeacetylase inhibitor of the invention. Preferably the animal is amammal, more preferably a human. Preferably, the histone deacetylaseinhibitor used according to this embodiment of the invention inhibits aprotozoal histone deacetylase to a greater extent than it inhibitsmammalian histone deacetylases, particularly human histone deacetylases.

The present invention further provides a method for treating a fungaldisease or infection comprising administering to an animal in need ofsuch treatment a therapeutically effective amount of a histonedeacetylase inhibitor of the invention. Preferably the animal is amammal, more preferably a human. Preferably, the histone deacetylaseinhibitor used according to this embodiment of the invention inhibits afungal histone deacetylase to a greater extent than it inhibitsmammalian histone deacetylases, particularly human histone deacetylases.

The term “therapeutically effective amount” is meant to denote a dosagesufficient to cause inhibition of histone deacetylase activity in thecells of the subject, or a dosage sufficient to inhibit cellproliferation or to induce cell differentiation in the subject.Administration may be by any route, including, without limitation,parenteral, oral, sublingual, transdermal, topical, intranasal,intratracheal, or intrarectal. In certain particularly preferredembodiments, compounds of the invention are administered intravenouslyin a hospital setting. In certain other preferred embodiments,administration may preferably be by the oral route.

When administered systemically, the histone deacetylase inhibitor ispreferably administered at a sufficient dosage to attain a blood levelof the inhibitor from about 0.01 μM to about 100 μM, more preferablyfrom about 0.05 μM to about 50 μM, still more preferably from about 0.1μM to about 25 μM, and still yet more preferably from about 0.5 μM toabout 25 μM. For localized administration, much lower concentrationsthan this may be effective, and much higher concentrations may betolerated. One of skill in the art will appreciate that the dosage ofhistone deacetylase inhibitor necessary to produce a therapeutic effectmay vary considerably depending on the tissue, organ, or the particularanimal or patient to be treated.

In certain preferred embodiments of the third aspect of the inventionthe method further comprises contacting the cell with an antisenseoligonucleotide that inhibits the expression of a histone deacetylase.The combined use of a nucleic acid level inhibitor (e.g., antisenseoligonucleotide) and a protein level inhibitor (i.e., inhibitor ofhistone deacetylase enzyme activity) results in an improved inhibitoryeffect, thereby reducing the amounts of the inhibitors required toobtain a given inhibitory effect as compared to the amounts necessarywhen either is used individually. The antisense oligonucleotidesaccording to this aspect of the invention are complementary to regionsof RNA or double-stranded DNA that encode HDAC-1, HDAC-2, HDAC-3,HDAC-4, HDAC-5, HDAC-6, HDAC7, and/or HDAC-8 (see e.g., GenBankAccession Number U50079 for HDAC-1, GenBank Accession Number U31814 forHDAC-2, and GenBank Accession Number U75697 for HDAC-3).

For purposes of the invention, the term “oligonucleotide” includespolymers of two or more deoxyribonucleosides, ribonucleosides, or2′-substituted ribonucleoside residues, or any combination thereof.Preferably, such oligonucleotides have from about 6 to about 100nucleoside residues, more preferably from about 8 to about 50 nucleosideresidues, and most preferably from about 12 to about 30 nucleosideresidues. The nucleoside residues may be coupled to each other by any ofthe numerous known internucleoside linkages. Such internucleosidelinkages include without limitation phosphorothioate,phosphorodithioate, alkylphosphonate, alkylphosphonothioate,phosphotriester, phosphoramidate, siloxane, carbonate,carboxymethylester, acetamidate, carbamate, thioether, bridgedphosphoramidate, bridged methylene phosphonate, bridged phosphorothioateand sulfone internucleoside linkages. In certain preferred embodiments,these internucleoside linkages may be phosphodiester, phosphotriester,phosphorothioate, or phosphoramidate linkages, or combinations thereof.The term oligonucleotide also encompasses such polymers havingchemically modified bases or sugars and/or having additionalsubstituents, including without limitation lipophilic groups,intercalating agents, diamines and adamantane.

For purposes of the invention the term “2′-substituted ribonucleoside”includes ribonucleosides in which the hydroxyl group at the 2′ positionof the pentose moiety is substituted to produce a 2′-O-substitutedribonucleoside. Preferably, such substitution is with a lower alkylgroup containing 1-6 saturated or unsaturated carbon atoms, or with anaryl or allyl group having 2-6 carbon atoms, wherein such alkyl, aryl orallyl group may be unsubstituted or may be substituted, e.g., with halo,hydroxy, trifluoromethyl, cyano, nitro, acyl, acyloxy, alkoxy, carboxyl,carbalkoxyl, or amino groups. The term “2′-substituted ribonucleoside”also includes ribonucleosides in which the 2′-hydroxyl group is replacedwith an amino group or with a halo group, preferably fluoro.

Particularly preferred antisense oligonucleotides utilized in thisaspect of the invention include chimeric oligonucleotides and hybridoligonucleotides.

For purposes of the invention, a “chimeric oligonucleotide” refers to anoligonucleotide having more than one type of internucleoside linkage.One preferred example of such a chimeric oligonucleotide is a chimericoligonucleotide comprising a phosphorothioate, phosphodiester orphosphorodithioate region, preferably comprising from about 2 to about12 nucleotides, and an alkylphosphonate or alkylphosphonothioate region(see e.g., Pederson et al. U.S. Pat. Nos. 5,635,377 and 5,366,878).Preferably, such chimeric oligonucleotides contain at least threeconsecutive internucleoside linkages selected from phosphodiester andphosphorothioate linkages, or combinations thereof.

For purposes of the invention, a “hybrid oligonucleotide” refers to anoligonucleotide having more than one type of nucleoside. One preferredexample of such a hybrid oligonucleotide comprises a ribonucleotide or2′-substituted ribonucleotide region, preferably comprising from about 2to about 12 2′-substituted nucleotides, and a deoxyribonucleotideregion. Preferably, such a hybrid oligonucleotide contains at leastthree consecutive deoxyribonucleosides and also containsribonucleosides, 2′-substituted ribonucleosides, preferably2′-O-substituted ribonucleosides, or combinations thereof (see e.g.,Metelev and Agrawal, U.S. Pat. No. 5,652,355).

The exact nucleotide sequence and chemical structure of an antisenseoligonucleotide utilized in the invention can be varied, so long as theoligonucleotide retains its ability to inhibit expression of the gene ofinterest. This is readily determined by testing whether the particularantisense oligonucleotide is active. Useful assays for this purposeinclude quantitating the mRNA encoding a product of the gene, a Westernblotting analysis assay for the product of the gene, an activity assayfor an enzymatically active gene product, or a soft agar growth assay,or a reporter gene construct assay, or an in vivo tumor growth assay,all of which are described in detail in this specification or inRamchandani et al. (1997) Proc. Natl. Acad. Sci. USA 94: 684-689.

Antisense oligonucleotides utilized in the invention may conveniently besynthesized on a suitable solid support using well known chemicalapproaches, including H-phosphonate chemistry, phosphoramiditechemistry, or a combination of H-phosphonate chemistry andphosphoramidite chemistry (i.e., H-phosphonate chemistry for some cyclesand phosphoramidite chemistry for other cycles). Suitable solid supportsinclude any of the standard solid supports used for solid phaseoligonucleotide synthesis, such as controlled-pore glass (CPG) (see,e.g., Pon, R. T. (1993) Methods in Molec. Biol. 20: 465-496).

Particularly preferred oligonucleotides have nucleotide sequences offrom about 13 to about 35 nucleotides which include the nucleotidesequences shown in Table 1. Yet additional particularly preferredoligonucleotides have nucleotide sequences of from about 15 to about 26nucleotides of the nucleotide sequences shown in Table 1.

TABLE 1 Accession position within Oligo Target Number NucleotidePosition Sequence Gene HDAC1 AS1 Human HDAC1 U50079 1585-16045′-GAAACGTGAGGGACTCAGCA-3′ 3′-UTR (SEQ ID NO: 1) HDAC1 AS2 Human HDAC1U50079 1565-1584 5′-GGAAGCCAGAGCTGGAGAGG-3′ 3′-UTR (SEQ ID NO: 2) HDAC1MM Human HDAC1 U50079 1585-1604 5′-GTTAGGTGAGGCACTGAGGA-3′ 3′-UTR (SEQID NO: 3) HDAC2 AS Human HDAC2 U31814 1643-16225′-GCTGAGCTGTTCTGATTTGG-3′ 3′-UTR (SEQ ID NO: 4) HDAC2 MM Human HDAC2U31814 1643-1622 5′-CGTGAGCACTTCTCATTTCC-3′ 3′-UTR (SEQ ID NO: 5) HDAC3AS Human HDAC3 AF039703 1276-1295 5′-CGCTTTCCTTGTCATTGACA-3′ 3′-UTR (SEQID NO: 6) HDAC3 MM Human HDAC3 AF039703 1276-12955′-GCCTTTCCTACTCATTGTGT-3′ 3′-UTR (SEQ ID NO: 7) HDAC4 AS1 Human HDAC4AB006626 514-33  5′-GCTGCCTGCCGTGCCCACCC-3′ 5′-UTR (SEQ ID NO: 8) HDAC4MM1 Human HDAC4 AB006626 514-33  5′-CGTGCCTGCGCTGCCCACGG-3′ 5′-UTR (SEQID NO: 9) HDAC4 AS2 Human HDAC4 AB006626 7710-29  5′-TACAGTCCATGCAACCTCCA-3′ 3′-UTR (SEQ ID NO: 10) HDAC4 MM4 Human HDAC4AB006626 7710-29   5′-ATCAGTCCAACCAACCTCGT-3′ 3′-UTR (SEQ ID NO: 11)HDAC5 AS Human HDAC5 AF039691 2663-2682 5′-CTTCGGTCTCACCTGCTTGG-3′3′-UTR (SEQ ID NO: 12) HDAC6 AS Human HDAC6 AJ011972 3791-38105′-CAGGCTGGAATGAGCTACAG-3′ 3′-UTR (SEQ ID NO: 13) HDAC6 MM Human HDAC6AJ011972 3791-3810 5′-GACGCTGCAATCAGGTAGAC-3′ 3′-UTR (SEQ ID NO: 14)HDAC7 AS Human HDAC7 AF239243 2896-2915 5′-CTTCAGCCAGGATGCCCACA-3′3′-UTR (SEQ ID NO: 15) HDAC8 AS1 Human HDAC8 AF230097 51-705′-CTCCGGCTCCTCCATCTTCC-3′ 5′-UTR (SEQ ID NO: 16) HDAC8 AS2 Human HDAC8AF230097 1328-1347 5′-AGCCAGCTGCCACTTGATGC-3′ 3′-UTR (SEQ ID NO: 17)

The following examples are intended to further illustrate certainpreferred embodiments of the invention, and are not intended to limitthe scope of the invention.

EXAMPLES

Example 14-{[4-Amino-6-(2-indanyl-amino)-[1,3,5]-triazin-2-yl-amino]-methyl}-N-(2-amino-phenyl)-benzamide(compound 8)

Step 1:Methyl-4-[(4,6-dichloro-[1,3,5]triazin-2-yl-amino)-methyl]-benzoate(compound 3)

To a stirred solution at −78° C. of cyanuric chloride 1 (8.23 g, 44.63mmol) in anhydrous THF (100 mL) under nitrogen was added a suspension ofmethyl 4-(aminomethyl)benzoate.HCl 2 (10.00 g, 49.59 mmol), in anhydrousTHF (50 mL), followed by i-Pr₂NEt (19.00 mL, 109.10 mmol). After 30 min,the reaction mixture was poured into a saturated aqueous solution ofNH₄Cl, and diluted with AcOEt. After separation, the organic layer wassuccessively washed with sat. NH₄Cl, H₂O and brine, dried over anhydrousMgSO₄, filtered and concentrated. The crude residue was then purified byflash chromatography on silica gel (AcOEt/CH₂Cl₂: 5/95) to afford thetitle compound 3 (12.12 g, 38.70 mmol, 87% yield) as a pale yellowsolid. ¹H NMR (300 MHz, CDCl₃) δ (ppm): AB system (δ_(A)=8.04,δ_(B)=7.38, J=8.5 Hz, 4H), 6.54 (bt, 1H), 4.76 (d, J=6.3 Hz, 2H), 3.93(s,3H).

Pathway A

Step 2:Methyl-4-[(4-amino-6-chloro-[1,3,5]triazin-2-yl-amino)-methyl]-benzoate(compound 4)

In a 150 mL sealed flask, a solution of 3 (6.00 g, 19.16 mmol) inanhydrous 1,4-dioxane (60 mL) was stirred at room temperature, saturatedwith NH₃ gas for 5 min, and warmed to 70° C. for 6 h. The reactionmixture was allowed to cool to room temperature, the saturation stepwith NH₃ gas was repeated at room temperature for 5 min, and thereaction mixture was warmed to 70° C. again for 18 h. Then, the reactionmixture was allowed to cool to room temperature, poured into a saturatedaqueous solution of NH₄Cl, and diluted with AcOEt. After separation, theorganic layer was successively washed with sat. NH₄Cl, H₂O and brine,dried over anhydrous MgSO₄, filtered and concentrated. The crude residuewas then purified by flash chromatography on silica gel (AcOEt/CH₂Cl₂:30/70) to afford the title compound 4 (5.16 g, 17.57 mmol, 91% yield) asa white solid. ¹H NMR (300 MHz, CDCl₃) δ (ppm): AB system (δ_(A)=8.01,δ_(B)7.35, J=8.1 Hz, 4H), 5.79 (bs, 1H), 5.40-5.20 (m, 2H), 4.72-4.63(m, 2H), 3.91 (s, 3H).

Pathway B

Step 2: Methyl4-[(4-chloro-6-(2-indanyl-amino)-[1,3,5]triazin-2-yl-amino)-methyl]-benzoate(compound 5)

To a stirred solution at room temperature of 3 (3.00 g, 9.58 mmol) inanhydrous THF (50 mL) under nitrogen were added i-Pr₂NEt (8.34 mL, 47.90mmol) and 2-aminoindan.HCl (1.95 g, 11.50 mmol) or R¹R²NH (1.2 equiv),respectively. After 18 h, the reaction mixture was poured into asaturated aqueous solution of NH₄Cl, and diluted with AcOEt. Afterseparation, the organic layer was successively washed with sat. NH₄Cl,H₂O and brine, dried over anhydrous MgSO₄, filtered and concentrated toafford the title compound 5 (4.06 g, 9.91 mmol, quantitative yield) as awhite powder. ¹H NMR (300 MHz, CDCl₃) δ (ppm): mixture of rotamers,8.06-7.94 (m, 2H), 7.43-7.28 (m, 2H), 7.24-7.12 (m, 4H), 6.41 and 6.05(2 bt, 1H), 5.68-5.44 (m, 1H), 4.92-4.54 (m, 3H), 3.92 (bs, 3H),3.41-3.12 (m, 2H), 2.90-2.70 (m, 2H).

Step 3:Methyl-4-[(4-amino-6-(2-indanyl-amino)-[1,3,5]triazin-2-yl-amino)-methyl]-benzoate(compound 6)

General Procedure for the Amination with NH₃ Gas:

In a 150 mL sealed flask, a solution of 5 (3.90 g, 9.51 mmol) inanhydrous 1,4-dioxane (80 mL) was stirred at room temperature, saturatedwith NH₃ gas for 5 min, and warmed to 140° C. for 6 h. The reactionmixture was allowed to cool to room temperature, the saturation stepwith NH₃ gas was repeated for 5 min, and the reaction mixture was warmedto 140° C. again for 18 h. Then, the reaction mixture was allowed tocool to room temperature, poured into a saturated aqueous solution ofNH₄Cl, and diluted with AcOEt. After separation, the organic layer wassuccessively washed with sat. NH₄Cl, H₂O and brine, dried over anhydrousMgSO₄, filtered and concentrated. The crude residue was then purified byflash chromatography on silica gel (MeOH/CH₂Cl₂: 3/97) to afford thetitle compound 6 (3.50 g, 8.96 mmol, 94% yield) as a pale yellow stickysolid. ¹H NMR (300 MHz, CDCl₃) δ (ppm): 7.99 (bd, J=8.2 Hz, 2H),7.41-7.33 (m, 2H), 7.24-7.13 (m,4H), 5.50-5.00 (m, 2H), 4.90-4.55 (m,5H), 3.92 (s, 3H), 3.40-3.10 (m, 2H), 2.90-2.70 (m, 2H), ¹³C NMR: (75MHz, CDCl₃) δ (ppm): 166.88, 167.35, 166.07, 144.77, 141.07, 129.82,128.93, 127.01, 126.61, 124.70, 52.06, 51.80, 44.25, 40.16. HRMS(calc.): 390.1804, (found): 390.1800.

Pathways A and B, Step 3, General Procedure with Primary and/orSecondary Amines

In a 50-75 mL sealed flask, a stirred solution of 4 (500 mg, 1.70 mmol,1 equiv), i-Pr₂NEt (1.48 mL, 8.51 mmol, 5 equiv) and R¹R²NH or R³R⁴NH(1.5-3 equiv) in anhydrous THF or 1,4-dioxane (20-30 mL) was warmed to120-140° C. for 15-24 h. Then, the reaction mixture was allowed to coolto room temperature, poured into a saturated aqueous solution of NH₄Cl,and diluted with AcOEt. After separation, the organic layer wassuccessively washed with sat. NH₄Cl, H₂O and brine, dried over anhydrousMgSO₄, filtered and concentrated. The crude residue was then purified byflash chromatography on silica gel to afford the title compound.

Step 4:4-[(4-Amino-6-(2-indanyl-amino)-[1,3.5triazin-2-yl-amino)-methyl]-benzoicacid (compound 7)

To a stirred solution at room temperature of 6 (2.07 g, 5.30 mmol) inTHF (50 mL) was added a solution of LiOH.H₂O (334 mg, 7.96 mmol) inwater (25 mL). After 18 h, the reaction mixture was diluted in water andacidified with 1 N HCl until pH 5-6 in order to get a white precipitate.After 1 h, the suspension was filtered off and the cake was abundantlywashed with water, and dried to afford the title compound 7 (1.73 g,4.60 mmol, 87% yield) as a white solid. ¹H NMR (300 MHz, acetone-d₆) δ(ppm): 8.05 (bd, J=8.1 Hz, 2H), 7.56-7.42 (m, 2H), 7.30-7.10 (m, 4H),5.90-5.65 (m, 2H), 4.85-4.60 (m, 4H), 3.40-2.80 (m, 4H). HRMS (calc.):376.1648, (found): 376.1651.

Step 5:4-{[4-Amino-6-indanyl-amino)-[1,3,5]-triazin-2-yl-amino]-methyl}-N-(2-amino-phenyl)-benzamide(compound 8)

To a stirred solution at room temperature of 7 (200 mg, 0.53 mmol) inanhydrous DMF (5 mL) under nitrogen were added Et₃N (74 μl, 0.53 mmol)and BOP reagent (282 mg, 0.64 mmol), respectively. After 40 min, asolution of 1,2-phenylenediamine (64 mg, 0.58 mmol), Et₃N (222 μl, 1.59mmol) in anhydrous DMF (2 mL) was added dropwise. After 1.5 h, thereaction mixture was poured into a saturated aqueous solution of NH₄Cl,and diluted with AcOEt. After separation, the organic layer wassuccessively washed with sat. NH₄Cl, H₂O and brine, dried over anhydrousMgSO₄, filtered and concentrated. The crude residue was then purified byflash chromatography on silica gel (MeOH/CH₂Cl₂: 2/98→5/95) to affordthe title compound 8 (155 mg, 0.33 mmol, 63% yield) as a pale yellowfoam. ¹H NMR (300 MHz, acetone-d₆) δ (ppm): 9.04 (bs, 1H), 7.96 (bd,J=8.0 Hz, 2H), 7.50-7.40 (m, 2H), 7.30 (dd, J=8.0 Hz, 1.4 Hz, 1H),7.22-7.08 (m, 4H), 6.99 (ddd, J=8.0 Hz, 7.5 Hz, 1.5 Hz, 1H), 6.86 (dd,J=8.0 Hz, 1.4 Hz, 1H), 6.67 (dt, J=7.5 Hz, 1.4 Hz, 1H), 6.60-5.49 (m,4H), 4.80-4.50 (m, 4H), 3.30-3.08 (m, 2H), 2.96-2.74 (m, 2H).

Examples 2-28

Examples 2 to 28 describe the preparation of compounds 9 to 35 using thesame procedure as described for compound 8 of Example 1.Characterization data are presented in Tables 2a and 2b.

TABLE 2a Characterization of Compounds Prepared in Examples 2-28

Ex. Cpd Y X Name Characterization Schm 2 9

NH₂ 4-[(4-amino-6-morpholin- 4-yl-[1,3,5]-triazin-2-ylamino)-methyl]-N-(2- amino-phenyl)- benzamide ′H NMR(CDCl₃)δ(ppm):8.02(s, 1H), 7.79(d, J=8.0 Hz, 2H), 7.34(d, J=8.0Hz, 2H), 7.31(m, 1H),7.08(dt, J=7.6Hz, 1.5 Hz, 1H), 6.82(t, J=6.7Hz, 2H), 5.62(t, J=5.9Hz,1H), 4.90(bs, 2H), 4.61(d, J=6.0Hz, 2H), 3.75-3.62(m, 10H). 1A 3 10

NH₂ 4-{[4-amino-6-(1-indanyl- amino)-[1,3,5]-triazin-2-ylamino]-methyl}-N-(2- amino-phenyl)- benzamide ¹HNMR(acetone-d₆)δ(ppm): 9.07(bs, 1H), 8.05-7.95(m, 2H), 7.55-7.45(m, 2H),7.37-7.10(m, 5H), 7.04(dt, J=7.6Hz, 1.6 Hz, 1H), 6.90(dd, J=8.0Hz,1.4Hz, 1H), 6.71(dt, J=7.6Hz, 1.4Hz, 1H), 6.65-5.55 (m, 5H),4.75-4.60(m, 3H), 3.05-2.75(m, 2H), 2.60-2.45(m, 1H)), 2.00-1.84(m, 1H).HRMS(calc.): 466.2229, (found): 466.2225 1A 4 11

NH₂ N-(2-Amino-phenyl)-4-{[4- amino-6-(4-phenyl- piperazin-1-yl)-[1,3,5]triazin-2-ylamino]- methyl}-benzamide ¹H NMR(acetone-d₆)δ(ppm):mixture of rotamers, 9.05-9.00(m, 1H), 7.98(d, J=8.8 Hz, 2H), 7.93(s),7.84(d, J=8.0Hz), 7.72 (d, J=8.2 Hz), 7.58-7.40(m, 3H), 7.31-7.19 (m,3H), 7.12-7.05(m), 6.98(d, J=8.1Hz, 2H), 6.86(d, J=8.2Hz, 1H), 6.80(t,J=7.1 Hz, 1H), 6.67(t, J=7.7Hz, 1H), 6.57-6.50 (m, 1H), 5.78- 5.60(m,2H), 4.67-4.64(m, 2H), 3.88-3.84(m, 4H), 3.14(s, 4H), HRMS(calc.):477.2389 [M⁺−NH₄], (found): 477.2383 1A 5 12

NH₂ 4-{[4-amino-6-(2- pyridinyl-methyl-amino)- [1,3,5]-triazin-2-ylamino]-methyl}-N-(2- amino-phenyl)- benzamide ¹HNMR(acetone-d₆)δ(ppm): 9.08(bs, 1H), 8.51(bs, 1H), 8.05-7.90(m, 2H),7.80-7.60(m, 1H), 7.55-7.15(m, 5H), 7.04 (dt, J=7.6Hz, 1.6Hz, 1H),6.90(dd, J=8.0 Hz, 1.4Hz, 1H), 6.71(dt, J=7.6Hz, 1.4Hz, 1H), 6.85-6.55(m, 1H), 5.84(bs, 2H), 4.75-4.60(m, 4H). HRMS(calc.): 441.2025,(found): 441.2029 1A 6 13

4-{[4,6-bis-(2-indanyl- amino)-[1,3,5]-triazin-2- ylamino]-methyl}-N-(2-amino-phenyl)- benzamide ¹H NMR(acetone-d₆)δ(ppm): 9.08(bs, 1H),8.05-7.95(m, 2H), 7.56-7.44(m, 2H), 7.34(bd, J=7.7Hz, 1H), 7.27-7.10(m,8H), 7.04(td, J=7.6Hz, 1.4Hz, 1H), 6.90(dd, J=8.0Hz, 1.4Hz, 1H),6.71(dt, J=7.6Hz, 1.4Hz, 1H), 6.65-5.90(m, 3H), 4.90-4.58 (m, 6H),3.40-2.80(m, 4H). HRMS(calc.): 582.2855, (found): 582.2838 1B 7 14

NH₂ 4-{[4-Amino-6-(9H- fluoren-9-ylamino)- [1,3,5]triazin-2-ylamino]-methyl}-N-(2-amino- phenyl)-benzamide ¹H NMR(acetone-d₆)δ(ppm):9.05-9.00 (m, 1H), 8.03-7.87(m, 2H), 7.80-7.70 (m, 2H), 7.63-7.20(m,9H), 7.00(t, 1H), 6.86 (d, 1H), 6.66(t, 1H), 6.50-5.50(m, 6H),4.75-4.55(m, 3H). HRMS(calc.): 514.2229, (found): 514.2232 1B 8 15

NH₂ N-(2-amino-phenyl)-4-[(4- amino-6-piperidin-1-yl- [1,3,5]-triazin-2-ylamino)-methyl]- benzamide ¹H NMR(CDCl₃)δ(ppm): 7.96(bs, 1H), 7.81(d,J=8.0Hz, 2H), 7.38(d, J=8.0 Hz, 2H), 7.32(d, J=8.0Hz, 1H), 7.08(dt,J=7.7 Hz, 1.4Hz, 1H), 6.83(t, J=6.6Hz, 2H), 5.47(bs, 1H), 4.80(bs, 2H),4.60(d, J=6.0 Hz, 2H), 3.88(bs, 2H), 3.67(t, J=5.2Hz, 4H), 1.66- 1.58(m,2H,), 1.56-1.48(m, 4H). 1A 9 16

NH₂ 4-[(4-amino-6- cyclopentyl-amino- [1,3,5]-triazin-2-yl-amino)-methyl]-N-(2- amino-phenyl)- benzamide ¹H NMR(CDCl₃)δ(ppm):7.97(bs, 1H), 7.82(d, J=8.0Hz, 2H), 7.39-7.34(m, 3H), 7.10(dt, J=7.6Hz,1.4Hz, 1H), 6.85(t, J=7.0Hz, 2H), 5.56(bs, 1H), 4.90(bs, 3H), 4.62(s,2H), 4.25-4.19(m, 1H) 3.88(bs, 2H), 1.95(m, 2H), 1.71-1.59(m, 4H),1.43-1.37(m, 2H). 1A 10 17

NH₂ (1R)-4-{[4-amino-6-(2- exo-fenchyl-amino)- [1,3,5]-triazin-2-ylamino]-methyl}-N-(2- amino-phenyl)- benzamide ¹HNMR(acetone-d₆)δ(ppm): 9.08(bs, 1H), AB system(δ_(A)=8.00, δ_(B)=7.51,J=8.0 Hz, 4H), 7.33(bd, J=7.7Hz, 1H), 7.03(ddd, J=8.0Hz, 7.3Hz, 1.4Hz,1H), 6.90(dd, J=8.0Hz, 1.4Hz, 1H), 6.71(dt, J=7.6Hz, 1.4, 1H),6.60-6.28(m, 1H), 5.80-5.20 (m, 3H), 4.67(bs, 4H), 3.87(bd, J=9.1Hz,1H), 1.80-1.60(m, 4H), 1.56-1.42(m, 1H), 1.34-1.00(m including 2 s, 8H),0.84(s, 3H). HRMS(calc.): 486.2855, (found): 486.2844 1A 11 18

4-{[4-allyl-amino-6-(2- indanyl-amino)-[1,3,5]- triazin-2-ylamino]-methyl}-N-(2-amino- phenyl)-benzamide ¹H NMR(acetone-d₆)δ(ppm): 9.07(bs,1H), 8.00(bd, J=7.4Hz, 2H), 7.58-7.42(m, 2H), 7.34(bd, J=8.0Hz, 1H),7.27-7.10 (m, 4H), 7.04(td, J=7.6Hz, 1.5Hz, 1H), 6.90 (dd, J=8.0, 1.4Hz,1H), 6.71(dt, J=7.6Hz, 1.4Hz, 1H), 6.60-5.70(m, 3H), 5.26-5.00 (m, 2H),4.86-4.54(m, 4H), 4.10-3.90(m, 2H), 3.38-3.10(m, 2H), 3.00-2.80(m, 2H).HRMS(calc.): 506.2542, (found): 506.2533 1B 12 19

4-{[4-cyclopropyl-amino- 6-(2-indanyl-amino)- [1,3,5]-triazin-2-ylamino]-methyl}-N-(2- amino-phenyl)- benzamide ¹HNMR(acetone-d₆)δ(ppm): 9.07(bs, 1H), 8.00(bd, J=7.7Hz, 2H), 7.60-7.40(m,2H), 7.33(dd, J=7.8Hz, 1.3Hz, 1H), 7.28-7.10(m, 4H), 7.04(dt, J=7.6Hz,1.5 Hz, 1H), 6.90(dd, J=7.8Hz, 1.4Hz, 1H), 6.71(dt, J=7.6Hz, 1.3Hz, 1H),6.67-5.80 (m, 2H), 4.90-4.50(m, 4H), 3.40-3.10(m, 2H), 3.05-2.70(m, 3H),0.75-0.43(m, 4H). HRMS(calc.): 506.2542, (found): 506.2548 1B 13 20

NH₂ 4-[(4-Amino-6- phenethylamino- [1,3,5]triazin-2-ylamino)-methyl]-N-(2-amino- phenyl)-benzamide ¹H NMR(acetone-d₆)δ(ppm): 9.03(s,1H), 7.97(d, J=7.7Hz, 2H), 7.55-7.40(m, 2H), 7.35-7.10(m, 6H), 6.99(td,J=8.0Hz, 1.3 Hz, 1H), 6.86(dd, J=8.0Hz, 1.3Hz, 1H), 6.67(dt, J=8.0Hz,1.4Hz, 1H), 6.62-5.40 (m, 5H), 4.75-4.45(m, 3H), 3.59-3.45(m, 2H),2.95-2.70(m, 2H). HRMS(calc.): 454.2229, (found): 454.2235 1A 14 21

NH₂ N-(2-Amino-phenyl)-4-{[4- amino-6-(3,4,5- trimethoxy- phenylamino)-methyl}-benzamide ¹H NMR(CDCl₃/MeOD)δ(ppm): 7.72(d, J=8.2Hz, 2H),7.21(d, J=8.2Hz, 2H), 7.04 (d, J=7.7Hz, 1H), 6.91(td, J=7.7Hz, 1.2 Hz,1H), 6.70-6.61(m, 4H), 4.61(bs, 2H), 3.58-3.52(m, 9H). 1B 15 22

NH₂ 4-{[4-Amino-6-(2,3- dihydro-indol-1-yl)- [1,3,5]triazin-2-ylamino]-methyl}-N-(2-amino- phenyl)-benzamide ¹H NMR(CDCl₃/MeOD)δ(ppm): 8.06(bs,1H), 7.82(d, J=8.0Hz, 2H), 7.37(d, J=8.2 Hz, 2H), 7.13(d, J=7.4Hz, 1H),7.06 (d, J=7.4Hz, 1H), 7.02-6.96(m, 2H), 6.84-6.71(m, 3H), 4.61(bs, 2H),4.03(t, J=8.5Hz, 2H), 3.02(t, J=8.5Hz, 2H). 1B 16 23

NH₂ 4-({4-Amino-6-[2-(2- methoxy-phenyl)- ethylamino]- [1,3,5]triazin-2-ylamino}-methyl)-N-(2- amino-phenyl)- benzamide ¹HNMR(acetone-d₆)δ(ppm): mixture of rotamers, 9.06(s, 1H), 7.96(d,J=8.0Hz, 2H), 7.55-7.40(m, 2H), 7.28(d, J=7.4 Hz, 1H), 7.21-6.70(m, 6H),6.67(t, J=7.4Hz, 1H), 6.60-5.70(m, 5H), 4.75-4.55(m, 3H), 3.81(s, 3H),3.55-3.45(m, 2H), 2.90-2.78 (m, 2H). HRMS(calc.): 484.2335, (found):484.2331 1A 17 24

NH₂ 4-({4-Amino-6-[2-(2- fluoro-phenyl)- ethylamino]- [1,3,5]triazin-2-ylamino}-methyl)-N-(2- amino-phenyl)- benzamide ¹HNMR(acetone-d₆)δ(ppm): mixture of rotamers, 9.03(s, 1H), 7.97(d,J=8.0Hz, 2H), 7.55-7.40(m, 2H), 7.38-7.17(m, 2H), 7.17-6.95(m, 4H),6.86(dd, J=8.0Hz, 1.4 Hz, 1H), 6.67(t, J=7.0Hz, 1H), 6.50-5.60 (m, 5H),4.75-4.55(m, 3H), 3.60-3.52(m, 2H), 2.95-2.85(m, 2H). HRMS(calc.):472.2135, (found): 472.2146 1A 18 25

4-{[4-benzyl-amino-6-(2- indanyl-amino)-[1,3,5]- triazin-2-ylamino]-methyl}-N-(2-amino- phenyl)-benzamide ¹H NMR(acetone-d₆)δ(ppm): 9.06(bs,1H), 8.04-7.93(m, 2H), 7.57-7.12(m, 12H), 7.04(td, J=7.6Hz, 1.5Hz, 1H),6.91 (dd, J=8.0Hz, 1.1Hz, 1H), 6.72(bt, J=7.6 Hz, 1H), 6.68-5.90(m, 3H),4.84-4.50(m, 7H), 3.35-3.13(m, 2H), 3.00-2.80(m, 2H). HRMS(calc.):556.2699, (found): 556.2706 1B 19 26

N-(2-Amino-phenyl)-4- [(4,6-di-piperidin-1-yl-[1,3,5]triazin-2-ylamino)- methyl]-benzamide ¹H NMR:(CDCl₃)δ(ppm):7.83(d, J=8.2 Hz, 3H), 7.44(d, J=8.2Hz, 2H), 7.32(d, J=7.4, 1H),7.12-7.06(m, 1H), 6.87-6.82 (m, 2H), 5.11(t, J=6.2Hz, 1H), 4.64(d,J=6.3Hz, 2H), 3.87(bs, 2H), 3.69(t, J=5.4 Hz, 8H), 1.63-1.53(m, 12H). 1B20 27

4-{[6-(2-indanyl-amino)- 4-phenethyl-amino- [1,3,5]-triazin-2-ylamino]-methyl}-N-(2- amino-phenyl)- benzamide ¹HNMR(acetone-d₆)δ(ppm): 9.07(bs, 1H), 8.05-7.90(m, 2H), 7.60-7.40(m, 2H),7.35-7.05(m, 10H), 7.04(td, J=7.6Hz, 1.5 Hz, 1H), 6.90(d, J=7.7Hz, 1H),6.71(t, J=7.3Hz, 1H), 6.60-5.70(m, 3H), 4.95-4.50(m, 5H), 3.70-2.80(m,8H). HRMS(calc.): 552.2750 [M⁺−NH₄], (found): 552.2746 1B 21 28

NH₂ 4-{[4-benzyl-amino-6-(2- indanyl-amino)-[1,3,5]- triazin-2-ylamino]-methyl}-N-(2-amino- phenyl)-benzamide ¹H NMR(CDCl₃)δ(ppm): 7.83(d, J=8.2Hz, 3H), 7.44(d, J=8.2Hz, 2H), 7.32(d, J=7.4, 1H), 7.12-7.06(m, 1H),6.87-6.82 (m, 2H), 5.11(t, J=6.2Hz, 1H), 4.64(d, J=6.3Hz, 2H), 3.87(bs,2H), 3.69(t, J=5.4 Hz), 1.63-1.53(m, 12H). 1A 22 29

NH₂ 4-[(4-Amino-6- benzylamino- [1,3,5]triazin-2-ylamino)-methyl]-N-(2-amino- phenyl)-benzamide ¹H NMR(acetone-d₆)δ(ppm): 9.04(s,1H), 7.95(d, J=7.3Hz, 2H), 7.45(d, J=7.1Hz, 2H), 7.38-7.15(m, 6H),7.00(td, J=8.0Hz, 1.5Hz, 1H), 6.86(dd, J=8.0Hz, 1.4Hz, 1H), 6.67(dt,J=8.0Hz, 1.4Hz, 1H), 6.67-6.25(m, 3H), 5.85-5.55(m, 3H), 4.61 (d,J=6.3Hz, 2H), 4.54(d, J=5.2Hz, 2H). HRMS(calc.): 440.2073, (found):440.2078 1A 23 30

4-{[6-(2-indanyl-amino)- 4-(3-pyridinyl-methyl-amino)-[1,3,5]-triazin-2- ylamino]-methyl}-N-(2- amino-phenyl)-benzamide ¹H NMR(acetone-d₆)δ(ppm): mixture of rotamers, 9.20-9.00(m,1H), 8.70-8.35(m, 2H), 8.05-7.90(m, 2H), 7.85-7.55(m, 1H), 7.55-7.10(m,8H), 7.04(dt, J=7.6Hz, 1.5 Hz, 1H), 6.91(bd, J=7.4Hz, 1H), 6.71(bt,J=7.3Hz, 1H), 6.80-6.00(m, 3H), 4.84-4.50(m, 7H), 3.34-3.12(m, 2H),3.00-2.80(m, 2H). HRMS(calc.): 539.2546 [M⁺−NH₄], (found): 539.2533 1B24 31

N-(2-Amino-phenyl)-4-[(4- piperidin-1-yl-6- pyrrolidin-1-yl-[1,3,5]triazin-2-ylamino)- methyl]-benzamide ¹H NMR(CDCl₃)δ(ppm):7.89(bs, 1H,), 7.82(d, J=8.2Hz, 2H), 7.42(d, J=8.0Hz, 2H), 7.32(d,J=8.0Hz, 1H), 7.09(dt, J=7.7 Hz, 1.6Hz, 1H), 6.87-6.82(m, 2H), 4.83 (bs,1H), 4.62(d, J=6.0Hz, 2H), 4.24(m, 1H), 3.88(bs, 1H), 2.04-1.96(m, 2H),1.70-1.52(m, 10H), 1.46-1.38(m, 2H). 1B 25 32

N-(2-Amino-phenyl)-4-{[2- piperidin-1-yl-6-(2- pyrrolidin-1-yl-ethylamino)-pyrimidin-4- ylamino]-methyl}- benzamide ¹HNMR(CDCl₃)δ(ppm): 8.27(bs, 1H), 7.74(d, J=7.4Hz, 2H), 7.29(m, 3H), 7.05(dt, J=7.6Hz, 1.4Hz, 1H), 6.81-6.76(m, 2H), 5.62(bs, 2H), 4.57(bs, 2H),3.91(bs, 2H), 3.69(m, 4H), 3.45(m, 2H), 2.57(t, J=6.2Hz, 2H), 2.47(m,4H), 1.71(m, 4H), 1.59-1.50(m, 6H). 1B 26 33

4-{[6-(2-indanyl-amino)- 4-morpholin-4-yl-[1,3,5]- triazin-2-ylamino]-methyl}-N-(2-amino- phenyl)-benzamide ¹H NMR(acetone-d₆)δ(ppm): 9.07(bs,1H), 8.08-7.95(m, 2H), 7.60-7.43(m, 2H), 7.33(d, J=8.0Hz, 1H),7.28-7.12(m, 4H), 7.04(dt, J=7.6Hz, 1.4Hz, 1H), 6.91(d, J=7.4Hz, 1H),6.72(t, J=7.4Hz, 1H), 6.55-6.05(m, 2H), 4.86-4.60(m, 5H), 3.80-3.56(m,8H), 3.38-3.12(m, 2H), 3.04-2.82(m, 2H). 1B 27 34

N-(2-Amino-phenyl)-4-{[2- piperidin-1-yl-6-(2- pyrrolidin-1-yl-ethylamino)-pyrimidin-4- ylamino]-methyl}- benzamide ¹HNMR(acetone-d₆)δ(ppm): 9.08(bs, 1H), 8.01(bd, J=7.4Hz, 2H), 7.56-7.43(m, 2H), 7.33(bd, J=8.0Hz, 1H), 7.28-7.12(m, 4H), 7.04(dt, J=7.6Hz,1.4Hz, 1H), 6.90 (dd, J=8.0Hz, 1.4Hz, 1H), 6.71(dt, J=7.6 Hz, 1.4Hz,1H), 6.65-5.75(m, 2H), 4.90-4.58(m, 5H), 3.66-2.34(m, 16H). 1B 28 35

NH₂ 4-({4-Amino-6-[2-(1H- indol-3-yl)-ethylamino]- [1,3,5]triazin-2-ylamino}-methyl)-N-(2- amino-phenyl)- benzamide ¹HNMR(acetone-d₆)δ(ppm): 10.00(s, 1H), 9.13(s, 1H), 7.93(d, J=8.0Hz, 2H),7.70-7.50(m, 1H), 7.50-7.22 (m, 4H), 7.18-6.91(m, 4H), 6.85(d, J=7.1Hz,1H), 6.67(t, J=7.4Hz, 1H), 6.40-5.90(m, 3H), 4.75-4.50(m, 2H), 4.37(s,2H), 3.62(d, J=6.3Hz, 2H), 2.99(s, 2H). 1A

TABLE 2b

Ex. Cpd X Y Name Characterization Schm 329 470

NH₂ 4-{[4-amino-6-(3- phenyl-propyl-1-amino)- [1,3,5]triazin-2-yl-amino]-methyl}-N- (2-amino-phenyl)- benzamide ¹H NMR(300 MHz,acetone-d₆)δ(ppm): 9.03(s, 1H), 7.96(d, J=8.2Hz, 2H), 7.46(d, J=7.7Hz,2H), 7.35-7.10(m, 6H), 7.00(t, J=7.7Hz, 1H), 6.86(d, J=8.0Hz, 1H), 6.67(t, J=7.7Hz, 1H), 6.60-5.40(m, 6H), 4.62 (s, 2H), 3.35(dd, J=12.1,6.9Hz, 2H), 2.75-2.60(m, 2H), 1.95-1.80(m, 2H). 1A 330 471

N-(2-amino-phenyl)-4- [(4-cyclopropyl-amino-6- phenethyl-amino-[1,3,5]triazin-2-yl- amino)-methyl]- benzamide ¹H NMR(300 MHz,acetone-d₆)δ(ppm): 9.04(s, 1H), 7.96(d, J=8.0Hz, 2H), 7.55-7.40(m, 2H),7.35-7.10(m, 6H), 6.98 (t, J=7.4Hz, 1H), 6.85(d, J=6.9Hz, 1H), 6.66(t,J=7.3Hz, 1H), 6.20-5.50(m, 3H), 4.80-4.50(m, 4H), 3.65-3.45(m, 2H),3.00-2.60(m, 2H), 0.80-0.40(m, 4H). 1B 331 472

N-(2-amino-phenyl)-4- {[4-cyclopropyl-methyl- amino-6-(2-indanyl-amino)-[1,3,5]-triazin-2- yl-amino]-methyl}- benzamide ¹H NMR(300 MHz,acetone-d₆)δ(ppm): 9.06(bs, 1H), 8.00(bd, J=7.1, 2H), 7.50 (bs, 1H), ),7.33(d, J=6.6Hz, 1H), 7.28-7.07(m, 4H), 7.03(td, J=7.6, 1.5Hz, 1H),6.90(dd, J=8.0, 1.4Hz, 1H), 6.71(td, J=7.6, 1.4Hz, 1H), 6.55-5.70(m,3H), 4.90-4.50(m, 5H), 3.40-2.80(m, 6H), 1.07 (bs, 1H), 0.44(bs, 2H),0.23(bs, 2H). 1B 332 473

n-BuNH N-(2-amino-phenyl)-4- [(4-n-butyl-amino-6- phenethyl-amino-[1,3,5]triazin-2-yl- amino)-methyl]- benzamide ¹H NMR(300 MHz,CDCl₃)δ(ppm): 8.08 (s, 1H), 7.83(d, J=6.6Hz, 2H), 7.45-7.05 (m, 8H),7.08(td, J=7.8, 1.5Hz, 1H), 6.84 (t, J=8.1Hz, 2H), 6.70-5.00(m, 3H),4.70-4.50(m, 2H), 3.65-3.50(m, 2H), 3.45-3.25(m, 2H), 2.40-2.25(m, 2H),1.60-1.45(m, 2H), 1.45-1.00(m, 2H), 1.00-0.8(m, 3). 1B 333 474

MeOCH₂CH₂NH N-(2-amino-phenyl)-4- {[4-(2-methoxy-ethyl-1-amino)-6-phenethyl- amino-[1,3,5]triazin-2-yl- amino]-methyl}- benzamide¹H NMR(300 MHz, acetone-d₆)δ(ppm): 9.02(s), 8.58(s), 8.40(dd, J=7.2,2Hz, 1H), 7.97(d, J=7.5Hz, 1H), 7.51-7.40(m, 2H), 7.70-6.90(m, 7H),6.86(dd, J=8.1, 1.2Hz), 6.76(dd, J=7.5, 1.8Hz), 6.67(td, J=7.8, 1.5 Hz),6.60-5.50(m, 3H), 4.75-4.55(m, 4H), 3.65-3.35(m, 6H), 3.35-3.20(s, 3H),2.95-2.75(m, 2H). 1B 334 475

N-(2-amino-phenyl)-4- {[4-(4-chloro-phenethyl- amino)-6-cyclopropyl-amino-[1,3,5]triazin-2-yl- amino]-methyl}- benzamide ¹H NMR(300 MHz,acetone-d₆)δ(ppm): 9.02(s, 1H), 8.02-7.91(m, 2H), 7.58-7.40 (m, 2H),7.28(s, 4H), 7.20-7.05(m, 1H), 6.99(td, J=7.5, 1.8Hz, 1H), 6.86(d, J=7.8Hz, 1H), 6.67(t, J=6.9Hz, 1H), 6.60-5.60 (m, 3H), 4.75-4.50(m, 4H),3.65-3.40(bs, 2H), 2.95-2.65(m, 2H), 0.75-0.55(m, 2H), 0.55-0.40(m, 2H).1B 335 476

N-(2-amino-phenyl)-4- {[6-cyclopropyl-amino- 4-(4-methoxy-phenethyl-amino)-[1,3,5]triazin-2- yl-amino]-methyl}- benzamide ¹H NMR(300 MHz,CDCl₃)δ(ppm): 8.55-7.72 (m, 4H), 7.55-6.75(m, 9H), 6.75-5.30(m, 3H),4.69(m, 2H), 3.85(s, 3H), 3.63(bs, 2H), 2.86(m, 3H), 0.85(bs, 2H),0.61(bs, 2H). 1B 336 477

N-(2-amino-phenyl)-4- {[4-(3-chloro-phenethyl- amino)-6-cyclopropyl-amino-[1,3,5]triazin-2-yl- amino]-methyl}- benzamide ¹H NMR(300 MHz,acetone-d₆)δ(ppm): 9.03(s, 1H), 7.96(d, J=7.5Hz, 2H), 7.60-7.37(m, 2H),7.37-7.12 (m, 5H), 6.99 (t, J=6.9Hz, 1H), 6.86(d, J=6.9Hz, 1H), 6.67(t,J=7.2Hz, 1H), 6.60-5.60(m, 3H), 4.75-4.50(m, 4H), 3.67-3.45(m, 2H),3.00-2.67(m, 3H), 0.75-0.40(m, 4H). 1B 337 478

N-(2-amino-phenyl)-4- {[6-cyclopropyl-amino- 4-(3,4-dimethoxy-phenethyl-amino)- [1,3,5]triazin-2-yl- amino]-methyl}- benzamide ¹HNMR(300 MHz, acetone-d₆)δ(ppm): 9.02(s, 1H), 7.96(d, J=8.1Hz, 2H),7.60-7.40(m, 2H), 7.29(d, J=8.1Hz, 1H), 6.99(td, J=8.1, 1.5Hz, 1H),6.95-6.72(m, 4H), 6.67(td, J=7.8, 1.5Hz, 1H), 6.20-5.60 (m, 3H),4.78-4.52(m, 4H), 3.75(s, 6H), 3.65-3.42(m, 2H), 2.95-2.65(m, 3H),0.72-0.40(m, 4H). 1B 338 479

N-(2-amino-phenyl)-4- {[6-cyclopropyl-amino- 4-(3-methoxy-phenethyl-amino)-[1,3,5]triazin-2- yl-amino]-methyl}- benzamide ¹H NMR(300 MHz,acetone-d₆)δ(ppm): 9.02(s, 1H), 7.96(d, J=7.8Hz, 2H), 7.60-7.35(m, 2H),7.29(d, J=7.5Hz, 1H), 7.18(t, J=7.8Hz, 1H), 6.99(td, J=7.5, 1.5 Hz, 1H),6.90-6.70(m, 4H), 6.67(t, J=7.8 Hz, 1H), 6.60-5.60(m, 3H), 4.77-4.50(m,4H), 3.76(s, 3H), 3.65-3.45(m, 2H), 2.92-2.65(m, 3H), 0.72-0.42(m, 4H).1B 339 480

N-(2-amino-phenyl)-4- {[6-cyclopropyl-amino- 4-(2-pyridin-2-yl-ethyl-1-amino)-[1,3,5]triazin- 2-yl-amino]-methyl}- benzamide ¹H NMR(300 MHz,acetone-d₆)δ(ppm): 9.03(s, 1H), 8.50(d, J=1.2Hz, 1H), 7.96(d, J=8.1Hz,2H), 7.66(t, J=7.5Hz, 1H), 7.60-7.40(m, 2H), 7.35-7.08(m, 3H), 6.99 (td,J=8.1, 1.5Hz, 1H), 6.86(dd, J=8.1, 1.5 Hz, 1H), 6.67(td, J=7.8, 1.5Hz,1H), 6.60-5.60(m, 3H), 4.75-4.50(m, 4H), 3.80-3.60(m, 2H), 3.15-2.90(m,2H), 2.90-2.65(m, 1H), 0.73-0.40(m, 4H). 1B 340 481

N-(2-amino-phenyl)-4- {[6-cyclopropyl-amino- 4-(3-pyridin-2-yl-ethyl-1-amino)-[1,3,5]triazin- 2-yl-amino]-methyl}- benzamide ¹H NMR(300 MHz,acetone-d₆)δ(ppm): 9.20-9.00(m, 1H), 8.70-8.50(m, 2H), 8.00 and 7.88(2d,J=7.9Hz, 2H), 7.75-7.43(m, 3H), 7.38-6.67(m, 5H), 6.22-5.78(m, 3H),4.80-4.55(m, 4H), 3.61(bs, 2H), 3.20-2.65(m, 3H), 0.80-0.45(m, 4H). 1B341 482

N-(2-amino-phenyl)-4- [(4-cyclopropyl-amino- 6-phenethyl-oxy-[1,3,5]triazin-2-yl- amino)-methyl]- benzamide ¹H NMR(300 MHz,acetone-d₆)δ(ppm): 9.04(s, 1H), 7.98(d, J=8.1Hz, 2H), 7.60-7.40(m, 2H),7.35-7.15(m, 6H), 7.00 (td, J=7.5, 1.5Hz, 1H), 6.86(d, J=8.1Hz, 1H),6.67(t, J=7.5Hz, 1H), 7.18-6.35(m, 2H), 4.75-4.30(m, 6H), 3.10-2.92(m,2H), 0.75-0.63(m, 2H), 0.57-0.48(m, 2H). 1, 25 342 483

Me N-(2-amino-phenyl)-4- [(6-methyl-4-phenethyl- amino-[1,3,5]triazin-2-yl-amino)-methyl]- benzamide ¹H NMR(300 MHz, acetone-d₆ +

DMSO-d₆)δ(ppm): mixture of rotamers, 9.62(bs, 1H), 8.03(d, J=8.0Hz, 2H),7.80-7.44(m, 3H), 7.40-7.10(m, 8H), 7.01(t, J=7.6Hz, 1H), 6.87(d,J=7.9Hz, 1H), 6.67(t, J=7.4Hz, 1H), 4.85(bs, 2H), 4.72-4.54(m, 2H),3.63-3.42(m, 2H), 2.96-2.74(m, 2H), 2.21 and 2.13(2s, 3H). 30 343 484

NH₂ N-(2-amino-phenyl)-4- {[4-amino-6-phenyl- [1,3,5]-triazin-2-yl-amino]-methyl}- benzamide ¹H NMR(300 MHz, acetone-d₆)δ(ppm): mixture ofrotamers, 9.08(bs, 1H), 8.48-8.36(m, 2H), 8.02(d, J=8.2Hz, 2H),7.63-7.42(m, 5H), 7.33 (d, J=7.7Hz, 1H), 7.19(bs, 1H), 7.03(t, J=7.4Hz,1H), 6.88 (d, J=7.9Hz, 1H), 6.70(t, J=7.6Hz, 1H), 6.35 and 6.25(2bs,2H), 4.87 and 4.75(2d, J=5.9Hz, 2H), 4.65(bs, 2H). 30 344 485

N-(2-amino-phenyl)-4- {[6-(2-indanyl-amino)-4- phenyl-[1,3,5]-triazin-2-yl-amino]-methyl}- benzamide ¹H NMR(300 MHz, acetone-d₆)δ(ppm): mixtureof rotamers, 9.14-8.96(m, 1H), 8.54-8.30(m, 2H), 8.09-7.95(m, 2H),7.68-7.40 (m, 5H), 7.38-7.08(m, 6H), 7.03 (t, J=7.3Hz, 1H), 6.94-6.76(m,2H), 6.71 (t, J=7.3Hz, 1H), 5.13-4.54(m, 5H), 3.49-3.18(m, 2H),3.12-2.90(m, 2H). 30

Example 29N-(2-Amino-phenyl)-4-({4-[2-(4-benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-[1,3,5]triazin-2-ylamino}-methyl)-benzamide(compound 39)

Step 1: N-Acetyl-1-piperonylpiperazine (compound 37)

To a stirred solution at 0° C. of 1-piperonylpiperazine 36 (5.00 g, 22.7mmol) in anhydrous CH₂Cl₂ (60 mL) was added Et₃N (6.33 mL, 45.4 mmol)followed by acetyl chloride (1.94 mL, 27.2 mmol). The reaction mixturewas stirred 30 min. at 0° C. and then 2 h at room temperature. Thereaction mixture was poured into a saturated aqueous solution of NH₄Cl,and diluted with AcOEt. After separation, the organic layer wassuccessively washed with sat. NH₄Cl, H₂O and brine, dried over anhydrousMgSO₄, filtered and concentrated. The crude residue was then purified byflash chromatography on silica gel (MeOH/CH₂Cl₂: 4/96) to afford thetitle compound 37 (5.52 g, 21.11 mmol, 93% yield) as a yellow solid. ¹HNMR: (300 MHz, CDCl₃) δ (ppm): 6.83 (s, 1H), 6.72 (m, 2H), 5.92 (s, 2H),3.59 (t, J=5.1 Hz, 2H), 3.44-3.40 (m, 4H), 2.42 (dt, J=5.1 Hz, 4H), 2.06(s, 3H).

Step 2:2-Chloro-4-morpholin-4-yl-6-[2-(4-benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-oxo-ethyl]-[1,3,5]triazine(compound 38)

To a stirred solution of 37 (3.00 g, 11.4 mmol) in anhydrous THF (25 mL)at −78° C. was slowly added a solution of LiHMDS (11.4 mL, 11.4 mmol, 1M in THF). The reaction mixture was stirred 1 h at −78 ° C. and asolution of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (2.69 g, 11.4mmol) in anhydrous THF (25 mL) was added. The reaction mixture wasslowly warmed up at room temperature and the reaction was quenched after16 h with a saturated aqueous solution of NH₄Cl. The THF was evaporatedand the residue was diluted with AcOEt. The organic layer wassuccessively washed with sat. NH₄Cl and brine, dried over anhydrousMgSO₄, filtered and concentrated. The crude residue was then purified byflash chromatography on silica gel (MeOH/CH₂Cl₂: 1/99→3/97) to affordthe title compound 38 (4.84 g, 10.49 mmol, 92% yield) as a pale yellowsolid. ¹H NMR (300 MHz, CDCl₃) δ (ppm): 6.84 (s, 1H), 6.77-6.69 (m, 2H),5.95 (s, 2H), 3.75-3.43 (m, 16H), 2.42 (m, 4H).

Step 3:N-(2-Amino-phenyl)-4-({4-[2-(4-benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-[1,3,5]triazin-2-ylamino}-methyl)-benzamide(compound 39)

The title compound 39 was obtained following the same procedure asExample 1, step 5. ¹H NMR (CDCl₃) δ (ppm): 7.96 (bs, 1H), 7.87 (d, J=8.2Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.5 Hz, 1H), 7.10 (dt, J=7.6Hz, 1.2 Hz, 1H), 6.87-6.81 (m, 3H), 6.75-6.68 (m, 2H), 5.93 (s, 2H),5.67 (bs, 1H), 4.64 (s, 2H), 3.90 (bs, 2H), 3.75-3.35 (m, 16H),2.45-2.30 (m, 4H).

Example 40 N-(2-aminophenyl)-6-(2-phenylamino-ethylamino)-nicotinamide(compound 44)

Step 1: N-(5-Bromo-pyridin-2-yl)-N′-phenyl-ethane-1,2-diamine (compound42)

A mixture of 2,5-dibromopyridine 40 (2.08 g, 8.6 mmol) andphenyl-1,2-ethyldiamine (1.98 g, 14.6 mmol, 1.7 equiv.) was stirredunder nitrogen at 120° C. for 6 h. After cooling down to roomtemperature, the solid mixture was ground in a mortar, dissolved inethyl acetate (200 mL), washed with saturated NaHCO₃ (2×50 mL), dried(MgSO₄), filtered and concentrated. After a quick purification through ashort chromatographic column (silica gel, elution 50% ether in hexanes),a pale yellow solid 42 (1.75 g, 6.01 mmol, 70% yield) was obtained. ¹³CNMR (300 MHz, acetone-d₆) δ (ppm): 158.6, 149.6, 148.8, 139.9, 129.8,117.1, 113.1, 110.8, 106.6, 43.9, 41.5. LMRS=294.0 (M+1).

Step 2: N-(2-aminophenyl)-6-(2-phenylamino-ethylamino)-nicotinamide(compound 44)

A mixture of 5-bromo-2-N-alkanyl-2-aminopyridine 42 (352 mg, 1.2 mmol),1,2-phenylenediamine (3.95 mmol, 3.3 equiv.), Pd(OAc)₂ (0.31 mmol, 26%mol) and 1,1′-bis (diphenylphosphino)ferrocene (124 mg, 0.22 mmol) wassuspended in degassed DMF (3 mL), treated with diisopropylethyl amine(0.9 mL, 5.2 mmol) and the system flushed with CO. The reaction mixturewas warmed up to 60° C. and stirred under CO (balloon) for 18 h at thistemperature. After evaporation of the DMF under vacuo, the residue waspurified through a chromatographic column (silica gel, elution 3% to 6%methanol in dichloromethane) to give 258 mg (0.74 mmol, 62% yield) ofthe aminoanilide 44. ¹H-NMR (CD₃OD-d4), δ (ppm): 8.67 (d, J=2.2 Hz, 1H),7.97 (dd, J=8.9 Hz, 2.5 Hz, 1H), 7.58 (m, 1H), 7.51 (m, 1H), 7.15 (dd,J=7.7 Hz, 1.1 Hz, 1H), 7.08 (m, 2H), 6,89 (dd, J=8.0 Hz, 1.4 Hz, 1H),6.76 (dt, J=7.7 Hz, 4.4 Hz, 1H), 6.67 (t, J=7.7 Hz, 2H), 6.60 (m, 2H),4.87 (bs, 4H), 3.60 (t, J=6.3 Hz, 2H), 3.35 (t, J=6.3 Hz, 2H).

Example 41 N-(2-amino-phenyl)-6-(4-methoxy-benzylamino)-nicotinamide(compound 45)

Step 1: N-(5-Bromo-pyridin-2-yl)-4-methoxybenzylamine (compound 43)

A mixture of 2,6-dibromopyridine 41 (6.03 mmol, 2 equiv.) andpara-methoxybenzyl amine (413 mg, 3.01 mmol) was stirred under nitrogenat 120° C. for 6 h. After identical work-up procedure described beforeand purification through a pad of silica gel (elution 50% ether inhexanes), a pale yellow solid 43 (773 mg, 2.60 mmol, 87% yield) wasobtained. ¹³C NMR (300 MHz, CDCl₃) δ (ppm): 159.1, 139.7, 132.1, 130.5,128.9, 127.2, 116.2, 114.3, 104.8, 55.4, 46.0. LMRS=295.0 (M+1).

Step 2: N-(2-amino-phenyl)-6-(4-methoxy-benzylamino)-nicotinamide(compound 45)

Following the procedure described in Example 40, step 2, butsubstituting 43 for 42, the title compound 45 was obtained in 61% yield.

Example 42N-(2-aminophenyl)-3-[6-(2-phenylamino-ethylamino)-pyridin-3-yl]-acrylamide(compound 50)

Step 2: 3-[6-(2-Phenylamino-ethylamino)-pyridin-3-yl)-acrylic acidtert-butyl ester (compound 46)

In a 50 mL flask, a mixture of 42 (308 mg, 1.05 mmol),tert-butylacrylate (0.8 mL, 5.5 mmol), diisopropylethylamine (0.8 mL,4.6 mmol), tri-o-tolylphosphine (POT, 192 mg, 0.63 mmol), Pd₂(dba)₃ (73mg, 0.08 mmol) in anhydrous DMF (4 mL) was stirred at 120° C. (preheatedoil bath) for 2 h under nitrogen. After DMF removal, the crude residuewas submitted to a chromatographic purification (column silica gel, 50%ether in hexanes) to afford 316 mg of 46 (88% yield). ¹³C NMR (300 MHz,CDCl₃) δ (ppm): 166.6, 159.3, 149.6, 147.8, 140.7, 134.9, 129.1, 119.8,117.3, 115.9, 112.6, 107.8, 80.0, 43.5, 40.9, 28.1. LRMS=340.3 (M+1).

Step 3: 3-[6-(2-Phenylamino-ethylamino)-pyridin-3-yl)-acrylic acid(compound 48)

Ester 46 (0.93 mmol) was dissolved 40% TFA in dichloromethane (10 mL)and the solution stirred at room temperature overnight. The solvent wasremoved under vacuo distilling with acetonitrile (3×10 mL) and storedunder high vacuum for 6 h. The solid residue 48 was employed for thenext reaction without further purification. LRMS=284.1 (M+1).

Step 4:N-(2-aminophenyl)-3-[6-(2-phenylamino-ethylamino)-pyridin-3-yl]-acrylamide(compound 50)

A mixture of acid 48 (0.93 mmol), BOP (495 mg, 1.12 mmol) and1,2-phenylenediamine (124 mg, 1.15 mmol) were dissolved in dryacetonitrile (4 mL) and treated with triethylamine (0.8 mL, 5.7 mmol).The solution was stirred under nitrogen at room temperature for 16 h.After concentration under vacuo, the crude was purified throughchromatographic column (5% methanol in dichloromethane), then wascrystallized from chloroform to give 50 (247 mg, 71% yield). ¹H-NMR(DMSO-d6), δ (ppm): 9.25 (bs, 1H), 8.21 (d, J=1.6 Hz, 1H), 7.67 (d,J=8.5 Hz, 1H), 7.43 (d, J=15.7 Hz, 1H), 7.32 (d, J=7.4 Hz, 1H), 7.24 (t,J=1.0 Hz, 1H), 7.08 (t, J=7.4 Hz, 2H), 6.91 (t, J=8.0 Hz, 1H), 6.75 (dt,J=8.0 Hz, 0.4 Hz, 1H), 6.57 (m, 6H), 5.20 (bs, 1H), 3.48 (t, J=6.3 Hz,2H), 3.33 (bs, 2H), 3.21 (t, J=6.3 Hz, 2H).

Example 43N-(2-aminophenyl)-3-[6-(4-methoxy-benzylamino)-pyridin-2-yl]-acrylamide(compound 51)

Step 2:N-(2-aminophenyl)-3-[6-(4-methoxy-benzylamino)-pyridin-2-yl]-acrylamide(compound 51)

Following the procedure described in Example 42, steps 2, 3, 4, butsubstituting 43 for 42, the title compound 51 was obtained in 50% yield(on 2 steps). ¹H-NMR (CDCl₃), δ (ppm): 7.60 (bs, 1H), 7.55 (bs, 1H),7.43 (t, J=7.7 Hz, 1H), 7.29 (d, J=8.3 Hz, 2H), 7.17 (d, J=15.1 Hz, 1H),7.06 (t, J=7.7 Hz, 1H), 6.88 (d, J=8.3 Hz, 2H), 6.80 (m, 2H), 6.70 (m,3H), 6.41 (d, J=8.5 Hz, 1H), 4.50 (d, J=5.5 Hz, 2H), 3.80 (s, 3H), 3.45(bs, 2H).

Example 44 4-[2-(2-amino-phenylcarbamoyl)-vinyl]-benzyl}-carbamic acidpyridin-3-yl methyl ester (compound 55)

Step 1: (4-bromo-benzyl)-carbamic acid pyridin-3-yl-methyl ester(compound 54)

4-bromobenzylamine HCl (3.0 g, 13.4 mmol) was dissolved in DMF (60 mL)at rt and then Et₃N (4.13 mL, 29.7 mmol) was added dropwise over 10 minto give cloudy solution. To this, DBU (2.42 mL, 16.2 mmol) and1,1′-carbonyl diimidazole (2.41 g, 14.8 mmol) were added. After beingstirred for 1 h at rt, 3-pyridylcarbinol (1.44 mL, 14.8 mmol) was addeddropwise over 10 min. The resulting reaction mixture was stirredovernight and then concentrated under reduced pressure. The residueobtained was diluted with ether/EtOAc (9:1) and then washed with H₂O.The organic layer was dried over Na₂SO₄, filtered and then concentratedto give the crude product which was recrystallized from EtOAc to give2.55 g of product 54 (59% yield, LRMS=323 (M+1).

Step 2: 4-[2-(2-amino-phenylcarbamoyl)-vinyl]-benzyl}-carbamic acidpyridin-3-yl methyl ester (compound 55)

Following the procedure described in Example 42, steps 2, 3, butsubstituting 54 for 42, and acrylic acid for tert-butyl acrylate thetitle compound 55 was obtained in an overall yield of 20%. ¹H NMR:(DMSO-d6) δ (ppm): 10.03 (s, 1H), 9.32 (s, 1H), 8.65 (s, 1H), 8.55 (d,J=3.3 Hz, 1H), 7.85 (d, J=7.69 Hz, 1H), 7.40-7.60 (m, 6H), 7.31 (d,J=7.69 Hz, 1H), 6.89 (dd, J=7.14 Hz, J=7 Hz, 1H), 6.71-6.79 (m, 2H),6.55 (dd, J=7.1 Hz, J=7 Hz, 1H), 5.20 (s, 2H), 4.93 (bs, 2H).

Example 45N-(2-aminophenyl)-3-{4-[(3,4,5-trimethoxy-benzylamino)-methyl]-phenyl}-acrylamide(compound 59)

Step 1: (4-Bromo-benzyl)-(3,4,5-trimethoxy-benzyl)-amine (compound 57)

To a stirred suspension of K₂CO₃ (522 mg, 3.77 mmol) in dry DMF wasadded 3,4,5-trimethoxybenzylamine (1.10 mL, 6.44 mmol, 2.2 equiv.)followed by a solution of p-bromo benzylbromide (0.73 g, 2.91 mmol) indry DMF (8 mL). The mixture was stirred at room temperature undernitrogen for two days in the dark, diluted with dichloromethane (200mL), washed with brine, dried (MgSO4), filtered and concentrated. Thecrude residue was purified by chromatographic column on silica gel(elution 5% methanol in dichloromethane) to give 2.59 mmol (89% yield)of dibenzylamine 57. ¹³C NMR (300 MHz, CDCl₃) δ (ppm): 152.5, 138.8,136.1, 135.4, 130.6, 129.2, 119.8, 104.2, 59.9, 55.3, 52.6, 51.7.LRMS=368.4 (M+1).

Step 2:N-(2-Nitro-phenyl)-3-{4-[(3,4,5-trimethoxy-benzylamino)-methyl]-phenyl}-acrylamide (compound 58)

Preparation of the Nitroacrylanilide

To a mixture of 2-nitroaniline (1.73 g, 12.5 mmol), DMAP (321 mg, 2.6mmol) and 2,6-di-tert-butyl-4-methylphenol (308 mg) in drydichloromethane (50 mL) at 0° C. was added triethylamine (10.6 mL, 76mmol) followed by acryloylchloride (3.2 mL, 38 mmol, 3.0 equiv.), andthe mixture was stirred at room temperature for 16 h. The solution wasdiluted with dichloromethane (250 mL), cooled to 0° C. and the excess ofreagent quenched with saturated NaHCO₃ (stirring for 1 h). The organiclayer was then washed (5% KHSO₄, then brine), dried (MgSO₄), filteredand concentrated under reduced pressure. After purification throughchromatographic column on silica gel (elution 50% ether in hexanes), 642mg (3.34 mmol, 27% yield) of the amide was obtained. ¹³C NMR (300 MHz,CDCl₃) δ (ppm): 163.6, 136.0, 135.6, 134.5, 131.3, 128.6, 125.4, 123.1,121.8. LRMS=193.2 (M+1).

Step 3:N-(2-aminophenyl)-3-{4-[(3,4,5-trimethoxy-benzylamino)-methyl]-phenyl}-acrylamide(59)

A mixture of nitro-compound 58 (127 mg, 0.27 mmol), SnCl₂ (429 mg, 2.26mmol, 8.4 equiv.) and NH₄OAc (445 mg) was suspended in methanol (9.5 mL)and water (1.5 mL), and the mixture was heated at 70° C. for 45 min. Themixture was diluted with ethylacetate (100 mL) and washed with brine andthen saturated NaHCO₃, dried (MgSO₄), filtered, and concentrated.Purification by chromatographic column on silica gel (elution 5 to 10%methanol in dichloromethane) gave 52 mg (43% yield) of 59. ¹H-NMR(CDCl₃), δ (ppm): 8.25 (bs, 1H), 7.59 (d, J=15.6 Hz, 1H), 7.38 (d, J=7.5Hz, 2H), 7.29 (d, J=7.5 Hz, 2H), 7.25 (m 1H), 7.02 (t, J=6.8 Hz, 1H),6.75 (m, 2H), 6.62 (d, J=15.6 Hz, 1H), 6.58 (s, 2H), 3.97 (bs, 3H), 3.80(s, 9H), 3.78 (s, 2H), 3.72 (s, 2H).

Example 46N-(2-aminophenyl)-3-(4-{[(3,4,5-trimethoxy-benzyl)-amino]-methyl}-phenyl)-acrylamide(compound 61)

Step 1:3-{4-{[Methyl-(3,4,5-trimethoxy-benzyl)-amino]-methyl}-phenyl)-N-(2-nitro-phenyl)acrylamide(compound 60)

Amine 58 (180.2 mg, 0.38 mmol) was dissolved in 88% of HCO₂H (6 mL),treated with excess of paraformaldehyde (7.67 mmol) and the mixturestirred at 70° C. for 2.5 h. A saturated NaHCO₃ solution, was addedslowly, extracted with dichloromethane (2×75 mL), dried (MgSO₄),filtered and concentrated. After chromatographic column on silica gel(elution 3 to 5% methanol in dichloromethane), pure N-methyl amine 60(118 mg, 63% yield) was obtained. ¹³C NMR (300 MHz, CDCl₃) δ (ppm):164.5, 153.1, 143.5, 142.3, 136.8, 136.1, 136.0, 135.3, 134.9, 132.9,129.3, 128.2, 125.8, 123.1, 122.2, 120.3, 105.4, 62.2, 61.2, 60.8, 56.0,42.5. LRMS=492.5 (M+1).

Step 2:N-(2-aminophenyl)-3-(4-{[(3,4,5-trimethoxy-benzyl)-amino]-methyl}-phenyl)-acrylamide(compound 61)

Following the procedure described in Example 45, step 3, butsubstituting the nitro-compound 60 for 58, the title compound 61 wasobtained in 72% yield. ¹H-NMR (DMSO-d6), δ (ppm): 9.15 (bs, 1H), 8.13(bs, 1H), 7.58 (d, J=1.9 Hz, 1H), 7.30 (m 4H), 7.12 (d, J=7.7 Hz, 1H),6.91 (m 3H), 6.75 (d, J=7.8 Hz, 1H), 6.57 (m 2H), 4.83 (bs, 2H), 4.43(d, J=5.5 Hz, 2H), 3.72 (s, 3H), 3.33 (s, 3H).

Example 47N-(2-aminophenyl)-3-{4-(4-methoxy-benzylamino)-phenyl}-acrylamide(compound 65)

Step 1: Methyl-3-(4-amino-phenyl)-acrylate hydrochloride (compound 63)

4-amino-cinnamic acid (10.41 g, 0.052 mol) was dissolved in methanol(100 mL) at rt. A solution of HCl in dioxane (15.6 mL, 4 N) was thenadded. The reaction mixture was heated at reflux overnight. The clearsolution was evaporated to a half volume and then settled down at rt.The white suspension obtained was collected by vacuum filtration. Themother liquid was evaporated again to a quart volume and cooled down tort. The suspension was filtered again. The combined the solid collectedfrom two filtration was dried in vacuo to give 7.16 g of 63 (64.3%yield). LRMS: 178 (M+1).

Step 2: Methyl-3-{4-(4-methoxy-benzylamino)-phenyl}-acrylatehydrochloride (compound 64)

To a suspension of compound 63 (3.57 g, 16.7 mmol) in DMF (30 mL) wasadded Et₃N. after 10 min 4-methoxybenzyl chloride (2.0 g, 12.8 mmol),Nal (0.38 g, 2.6 mmol) and K₂CO₃ (3.53 g, 25.5 mmol) were addedsuccessively. The mixture was heated at 60° C. overnight and evaporatedto dryness. The residue was partitioned between NaHCO₃ sat. solution (50mL) and EtOAc (50 mL×3). The combined organic layers were washed withbrine and then evaporated to dryness. The residue was purified by flashchromatography and then recrystallized from isopropylalcohol to give1.16 g 64 (yield 30.6%, LRMS=298) and 1.46 g of 63 (49% recoveredyield).

Step 3:N-(2-aminophenyl)-3-{4-(4-methoxy-benzylamino)-phenyl}-acrylamide(compound 65)

Following the procedure described in Example 42, step 4, butsubstituting 64 for 48, the title compound 65 was obtained in 32% yield.¹H NMR: (DMSO-d6) δ (ppm): 9.15 (s, 1H), 7.24)-7.38 (m, 6H), 6.84-6.90(m, 3H), 6.72 (m, 2H), 6.49-6.60 (m, 4H), 4.84 (s, 2H), 4.22 (d, J=5.77Hz, 2H).

Example 48 N-(2-Amino-phenyl)-3-(4-styrylamino-phenyl)-acrylamide(compound 71)

Step 1: N-(4-Iodo-phenyl)-(3-phenyl-allyl)-amine (compound 69)

Following the procedure described in Example 47, step 2, butsubstituting 68 for 63, the title compound 69 was obtained in 70% yield.LRMS=288 (M+1)

Step 2: N-(2-Amino-phenyl)-3-(4-styrylamino-phenyl)-acrylamide (71)

Following the procedure described in Example 42, steps 2, 4, butsubstituting 69 for 42, and acrylic acid for tert-butyl acrylate thetitle compound 71 was obtained in an overall yield of 60%. ¹H NMR:(DMSO-d₆) δ (ppm): 9.22 (bs, 1H), 7.45 (d, J=6.9 Hz, 2H), 7.39 (d, J=9.0Hz, 2H), 7.34 (d, J=7.4 Hz, 2H), 7.26 (dt, J=7.4 Hz, 6.8 Hz, 2H), 6.93(dt, J=7.9 Hz, 7.1 Hz, 1H), 6.78 (d, J=7.9 Hz, 1H), 6.69 (d, J=8.5 Hz,2H), 6.63-6.55 (m, 4H), 6.44-6.37 (m, 1H), 4.95 (bs, 2H), 3.95 (bs, 2H).

Example 49 N-(2-Amino-phenyl)-3-[4-(4-methoxy-benzamide)]-acrylamide(compound 72)

Step 1: N-(4-Iodo-phenyl)-4methoxy-benzamide (compound 70)

Following the procedure described in Example 47, step 2, butsubstituting 68 for 63, the title compound 70 was obtained in 90% yield.LRMS=354.0 (M+1)

Step 2: N-(2-Amino-phenyl)-3-[4-(4-methoxy-benzamide)]-acrylamide(compound 72)

Following the procedure described in Example 42, steps 2, 4, butsubstituting 70 for 42, and acrylic acid for tert-butyl acrylate thetitle compound 72 was obtained in an overall yield of 90%. ¹H NMR:(DMSO-d₆) δ (ppm): 9.4 (bs, 1H), 7.60(d, J=8.5 Hz, 1H), 7.54-7.45 (m,3H), 7.87 (d, J=7.7 Hz, 1H), 7.10 (d, J=8.8 Hz, 1H), 6.95-6.77 (m, 3H),6.62 (d, J=7.7 Hz, 2H), 6.08-6.04 (m, 2H), 4.98 (bs, 2H), 3.72 (s, 3H).

Example 50N-(2-aminophenyl)-3-{6-[2-(4-oxo-4H-quinazolin-3-yl)-ethylamino]-pyridin-3-yl}-acrylamide(compound 76)

Step 1: N-(5-Bromo-pyridin-2-yl)-ethane-1,2-diamine (compound 73)

Following the procedure described in Example 40, step 1, but using1,2-diaminoethane as alkyl amine, the title compound 73 was obtained in84% yield. ¹³C NMR (300 MHz, CD₃OD): 159.1, 148.7, 140.7, 111.7, 107.2,44.3, 41.7. LRMS=218.1 (M+1)

Step 2: 3-[2-(5-Bromo-pyridin-2-ylamino)-ethyl]-3H-quinazolin-4-one(compound 75)

A suspension of primary amine 73 (1.17 g, 5.40 mmol) and isatoicanhydride 74 (880 mg, 5.40 mmol) in methanol (25 mL) was stirred for 3 hat 50° C. and then concentrated. The resulting oily residue wasdissolved in 88% formic acid (20 mL) and refluxed overnight. Afterremoval of formic acid, the solid residue was purified through columnchromatography on silica gel (5% methanol in dichloromethane) to give1.24 g (3.6 mmol, 67% yield) of 75. ¹³C NMR (300 MHz, CDCl₃): 161.6,156.8, 147.7, 147.6, 147.2, 139.8, 134.5, 127.4, 126.8, 126.3, 121.6,110.1, 107.0, 46.3, 40.1. LRMS=347.1 (M+1). Step 3:N-(2-aminophenyl)-3-{6-[2-(4-oxo-4H-quinazolin-3-yl)-ethylamino]-pyridin-3-yl}-acrylamide(compound 76)

Following the procedure described in Example 42, steps 2 to 4, butsubstituting 75 for 42, the title compound 76 was obtained in an overallyield of 68%. ¹H-NMR (DMSO-d6), δ (ppm): 9.24 (bs, 1H), 8.17 (dd, J=8.0Hz, 1.6 Hz, 1H), 8.11 (bs, 1H), 8.08 (d, J=1.9 Hz, 1H), 7.82 (dt, J=8.5Hz, 1.4 Hz, 1H), 7.64 (d, J=8.2 Hz, 2H), 7.25 (t, J=5.8 Hz, 1H), 6.90(dt, J=15.7 Hz, 1H), 6.74 (dd, J=8.0 Hz, 1.4 Hz, 1H), 6.58 (m, 3H), 4.95(bs, 2H), 4.17 (t, J=5.2 Hz, 2H), 3.68 (m, J=5.2 Hz, 2H).

Example 51N-(2-aminophenyl)-3-{6-[2-(4-benzyl-2,6-dioxo-piperazin-1-yl)-ethylamino]-pyridin-3-yl}-acrylamide(compound 78)

Step 2:4-Benzyl-1-[2-(5-bromo-pyridin-2-ylamino)-ethyl]-piperazine-2,6-dione(compound 77)

A suspension of benzyliminodiacetic acid (702 mg, 3.15 mmol) and aceticanhydride (15 mL) was stirred at 120° C. for 45 min. The reactionmixture was diluted with dry toluene and concentrated in vacuo to removethe volatiles. The residue was dissolved in dry toluene (15 mL) andtransferred via cannula to a reaction flask containing the amine 73 (475mg, 3.2 mmol). The mixture was heated at 90° C. for 16 h, concentratedand chromatographed by column on silica gel (elution 5% methanol indichloromethane) to give 684 mg (1.70 mmol, 54% yield) of 77.

Step 3:N-(2-aminophenyl)-3-{6-[2-(4benzyl-2.6-dioxo-piperazin-1-yl)-ethylamino]-pyridin-3-yl}-acrylamide(compound 78)

Following the procedure described in Example 42, steps 2 to 4, butsubstituting 77 for 42, the title compound 78 was obtained in an overallyield of 60%. ¹H-NMR (CD₃OD-d4), δ (ppm): 8.09 (d, J=1.8 Hz, 1H), 7.68(dd, J=8.7 Hz, 2.1 Hz, 1H), 7.53 (d, J=15.6 Hz, 1H), 7.29 (m, 6H), 7.20(dd, J=7.8 Hz, 1.2 Hz, 1H), 7.02 (dt, J=9.0 Hz, 1.2 Hz, 1H), 6.86 (dd,J=8.1 Hz, 1.2 Hz, 1H), 6.73 (dt, J=7.5 Hz, 1.5 Hz, 1H), 6.61 (d, J=15.6Hz, 1H), 6.50 (d, J=8.7 Hz, 1H), 4.85 (bs, 3H), 3.97 (t, J=7.5 Hz, 2H),3.60 (s, 2H), 3.57 (t, J=7.5 Hz, 2H), 3.38 (s, 4H).

Example 52(E)-4-{[4-Amino-6-(2-indanyl-amino)-[1,3,5]triazin-2-yl-amino]-methyl}-N-(2-amino-phenyl)-cinnamide(compound 83)

Step 1: 4,6-Dichloro-2-(2-indanyl-amino)-[1,3,5]triazine (compound 79)

To a stirred solution at −78° C. of cyanuric chloride (13.15 g, 71.33mmol) in anhydrous THF (100 mL) under nitrogen was slowly canulated asolution of 2-aminoindan (10.00 g, 75.08 mmol), i-Pr₂NEt (14.39 mL,82.59 mmol) in anhydrous THF (60 mL). After 50 min, the reaction mixturewas poured into a saturated aqueous solution of NH₄Cl, and diluted withAcOEt. After separation, the organic layer was successively washed withsat. NH₄Cl, H₂O and brine, dried over anhydrous MgSO₄, filtered andconcentrated. The crude residue was then purified by flashchromatography on silica gel (AcOEt/CH₂Cl₂: 2/98→5/95) and byco-precipitation (AcOEt/hexanes) to afford the title compound 79 (18.51g, 65.78 mmol, 92% yield) as a beige powder. ¹H NMR (300 MHz, CDCl₃) δ(ppm): 7.29-7.18 (m, 4H), 6.02 (bd, J=6.3 Hz, 1H), 4.94-4.84 (m, 1H),3.41 (dd, J=16.2, 6.9 Hz, 2H), 2.89 (dd, J=16.1, 4.5 Hz, 2H).

Step 2:2-(4-Bromo-benzyl-amino)-4-chloro-6-(2-indanyl-amino)-[1,3,5]triazine(compound 80)

To a stirred solution at room temperature of 79 (2.68 g, 9.52 mmol) inanhydrous THF (50 mL) under nitrogen were added i-Pr₂NEt (4.79 mL, 27.53mmol) and 4-bromobenzylamine.HCl (2.45 g, 11.01 mmol), respectively.After 17 h, the reaction mixture was poured into a saturated aqueoussolution of NH₄Cl, and diluted with AcOEt. After separation, the organiclayer was successively washed with sat. NH₄Cl, H₂O and brine, dried overanhydrous MgSO₄, filtered and concentrated. The crude residue was thenpurified by flash chromatography on silica gel (AcOEt/CH₂Cl₂: 3/97→5/95)to afford the title compound 80 (4.00 g, 9.29 mmol, 97% yield) as awhite powder. ¹H NMR (300 MHz, CDCl₃) δ (ppm): mixture of rotamers,7.52-7.42 (m, 2H), 7.26-7.11 (m, 6H), 6.51 and 6.12 (2 m, 1H), 5.72-5.46(m, 1H), 4.94-4.64 (m, 1H), 4.62-4.46 (m, 2H), 3.43-3.16 (m, 2H),2.92-2.74 (m, 2H).

Step 3:4-Amino-2-(4-bromo-benzyl-amino)-6-(2-indanyl-amino)-[1,3,5]triazine(compound 81)

In a 75 mL sealed flask, a solution of 80 (2.05 g, 4.76 mmol) inanhydrous 1,4-dioxane (60 mL) was stirred at room temperature, saturatedwith NH₃ gas for 5 min, and warmed to 140° C. for 18 h. The reactionmixture was allowed to cool to room temperature, the saturation stepwith NH₃ gas was repeated for 5 min, and the reaction mixture was warmedto 140° C. again for 24 h. Then, the reaction mixture was allowed tocool to room temperature, poured into 1N HCl, and diluted with AcOEt.After separation, the organic layer was successively washed with at.NH₄Cl, H₂O and brine, dried over anhydrous MgSO₄, filtered andconcentrated. The crude residue was then purified by flashchromatography on silica gel (MeOH/CH₂Cl₂: 5/95) to afford the titlecompound 81 (1.96 g, 4.76 mmol, quantitative yield) as a colorless foam.¹H NMR (300 MHz, CDCl₃) δ (ppm): 7.43 (d, J=8.2 Hz, 2H), 7.25-7.12 (m,6H), 5.70-5.10 (m, 2H), 5.00-4.65 (m, 3H), 4.52 (bs, 2H), 3.40-3.10 (m,2H), 2.90-2.65 (m, 2H).

Step 4:(E)-4-{[4-Amino-6-(2-indanyl-amino)-[1,3,5]triazin-2-yl-amino]-methyl}-N-[2-(N-t-butoxycarbonyl)-amino-phenyl]-cinamide(compound 82)

Preparation of N-[2-(N-t-Butoxycarbonyl)-amino-phenyl]-acrylamide

Following the procedure described in Example 45, step 2, butsubstituting the nitro-compound 2-(N-t-butoxycarbonyl)-amino-aniline for2-nitroaniline, the title compound was obtained in 77% yield. ¹H NMR(300 MHz, CDCl₃) δ (ppm): 8.51 (bs, 1H), 7.60-7.45 (m, 1H), 7.38-7.28(m, 1H), 7.20-7.05 (m, 2H), 6.98 (bs, 1H), 6.41 (dd, J=17.0 Hz, 1.1 Hz,1H), 6.25 (dd, J=16.9 Hz, 10.0 Hz, 1H), 5.76 (dd, J=10.2 Hz, 1.4 Hz,1H), 1.52 (s, 9H).

In a 50 mL sealed flask, a solution of 81 (300 mg, 0.73 mmol), theacrylamide (230 mg, 0.88 mmol), Et₃N (407 μl, 2.92 mmol),tri-o-tolylphosphine (POT, 13 mg, 0.04 mmol), Pd₂(dba)₃ (20 mg, 0.02mmol) in anhydrous DMF (10 mL) was stirred at room temperature,saturated with N₂ gas for 15 min, and warmed to 100° C. for 15 h. Then,the reaction mixture was allowed to cool to room temperature, pouredinto a saturated aqueous solution of NH₄Cl, and diluted with AcOEt.After separation, the organic layer was successively washed with sat.NH₄Cl, H₂O and brine, dried over anhydrous MgSO₄, filtered andconcentrated. The crude residue was then purified by flashchromatography on silica gel (MeOH/CH₂Cl₂: 2/98→5/95) to afford thetitle compound 82 (240 mg, 0.41 mmol, 56% yield) as a beige solid. ¹HNMR (300 MHz, CDCl₃) δ (ppm): 8.46 (bs, 1H), 7.71 (bd, J=15.7 Hz, 1H),7.62-7.05 (m, 13H), 6.54 (bd, J=15.9 Hz, 1H), 5.95-4.90 (m, 4H),4.85-4.48 (m 3H), 3.40-3.14 (m, 2H), 2.90-2.70 (m, 2H), 1.52 (s, 9H).

Step 5:(E)-4-{[4-Amino-6-(2-indanyl-amino)-[1,3,5]triazin-2-yl-amino]-methyl}-N-(2-amino-phenyl)-cinnamide(compound 83)

To a stirred solution at room temperature of 82 (230 mg, 0.39 mmol) inCH₂Cl₂ (5 mL) was added TFA (1 mL, 95% in water). After 18 h, thereaction mixture was poured into a saturated aqueous solution of NaHCO₃,and diluted with AcOEt. After separation, the organic layer wassuccessively washed with sat. NaHCO₃, H₂O and brine, dried overanhydrous MgSO₄, filtered and concentrated. The crude residue was thenpurified by flash chromatography on silica gel (MeOH/CH₂Cl₂: 5/95) toafford the title compound 83 (170 mg, 0.35 mmol, 89% yield) as a yellowsolid. ¹H NMR (300 MHz, acetone-d₆) δ (ppm): 8.87 (bs, 1H), 7.69 (d,J=15.7 Hz, 1H), 7.59 (bd, J=7.7 Hz, 2H), 7.49-7.34 (m, 3H), 7.28-7.11(m, 4H), 7.05-6.91 (m, 2H), 6.88 (dd, J=8.0, 1.4 Hz, 1H), 6.69 (td,J=7.6, 1.4 Hz, 1H), 6.65-5.50 (m, 4H), 4.83-4.53 (m, 5H), 3.34-3.11 (m,2H), 2.98-2.80 (m, 2H).

Example 53N-(2-aminophenyl)-2-(4-methoxy-benzylamino)-quinolin-6-yl-amide(compound 87)

Step 1: 2,6-ditrifluoromethanesulfonyloxy-quinoline (compound 85)

A solution of 2,6-dihydroxyquinoline 84 (1.254 g, 7.78 mmol) and DMAP (afew crystals) in dry pyridine (15 mL) was treated with neattrifluoromethanesulfonic anhydride (5.2 g, 18,4 mmol, 1.2 equiv.) andstirred at 0° C. for 5 h. This solution was then poured on a mixturebrine/sat NaHCO₃ and extracted with dichloromethane (2×150 mL), dried(MgSO₄), filtered and concentrated. Purification by columnchromatography on silica gel (30% to 50% ether in hexanes) gave 2.58 g(6.1 mmol, 78% yield) of 85. ¹³C NMR (300 MHz, CDCl₃): 154.5, 147.8,144.6, 142.0, 131.6, 127.8, 124.9, 119.3, 118.7, 114.9. LRMS=426.0(M+1).

Step 2: N-(2-aminophenyl)-2-(4-methoxy-benzylamino)-quinolin-6-yl-amide(compound 87)

Following the procedure described in Example 40, steps 1, 2, butsubstituting 85 for 40, the title compound 87 was obtained in 92% yield.¹H-NMR (DMSO-d6), δ (ppm): 9.66 (bs, 1H), 8.32 (s, 1H), 8.05 (d, J=8.8Hz, 1H), 7.96 (dd, J=9.1 Hz, 2.2 Hz, 1H), 7.72 (d, J=2.2 Hz, 1H), 7.55(dd, J=8.5 Hz, 2.2 Hz, 1H), 7.34 (dd, J=8.5 Hz, 2.2 Hz, 1H), 7.20 (d,J=7.7 Hz, 1H), 6.97 (t, J=7.7 Hz, 1H), 6.90 (m 2H), 6.80 (d, J=7.9 Hz,1H), 6.61 (t, J=6.3 Hz, 1H), 4.90 (bs 2H, 4.58 (d, J=3.3 Hz, 2H), 3.73(s, 3H), 3.33 (bs, 1H).

Example 54N-(2-aminophenyl)-3-[2-(4-methoxy-benzylamino)-quinolin-6-yl]-acrylamide(compound 88)

Step 3:N-(2-aminophenyl)-3-[2-(4-methoxy-benzylamino)-quinolin-6-yl]-acrylamide(compound 88)

Following the procedure described in Example 42, steps 1 to 4, butsubstituting 85 for 40, the title compound 88 was obtained in an overallyield of 71%. ¹H-NMR (DMSO-d6), δ (ppm): 9.70 (bs, 1H), 9.40 (bs, 1H),8.20 (d, J=8.9 Hz, 1H), 8.03 (bs, 2H), 7.94 (d, J=7.2 Hz, 1H), 7.64 (dd,J=15.7 Hz, 2.5 Hz, 1H), 7.41 (d, J=8.5 Hz, 2H), 7.39 (m, 1H), 7.14 (d,J=8.9 Hz, 1H), 7.05 (d, J=15.7 Hz, 1H), 6.97 (m, 1H), 6.95 (d, J=8.5 Hz,2H), 6.81 (d, J=8.0 Hz, 1H), 6.65 (t, J=7.2 Hz, 1H), 4.76 (s, 2H), 3.75(s, 3H).

Examples 55-84

Examples 55 to 84 describe the preparation of compounds 89 to 118 usingthe same procedures as described for compounds 44 to 88 in Examples 40to 54. Characterization data are presented in Tables 3a-d.

TABLE 3a Characterization of Compounds Prepared in Examples 42-84

Ex. Cpd. W Y Z R Name Characterization Schm 42  50

N CH H N-(2-aminophenyl)-3-[6- (2-phenylamino- ethylamino)-pyridin-3-yl]-acrylamide ¹H-NMR(DMSO-d6), δ(ppm): 9.25(bs, 1H), 8.21(d, J=1.6Hz,1H), 7.67(d, J=8.5 Hz, 1H), 7.43(d, J=15.7Hz, 1H), 7.32(d, J=7.4Hz, 1H),7.24(t, J=1.0Hz, 1H), 7.08 (t, J=7.4Hz, 2H), 6.91(t, J=8.0Hz, 1H),6.75(dt, J=8.0Hz, 0.4Hz, 1H), 6.57(m, 6H), 5.20(bs, 1H), 3.48(t,J=6.3Hz, 2H), 3.33(bs, 2H), 3.21(t, J=6.3Hz, 2H) 3 44  55b

CH CH H {4-[2-(2-amino-phenyl- carbamoyl)-vinyl]- phenyl}-carbamic acidpyridin-3-yl methyl ester ¹H NMR:(DMSO-d6)δ(ppm): 10.03(s, 1H), 9.32(s,1H), 8.65(s, 1H), 8.55(d, J=3.3Hz, 1H), 7.85(d, J=7.69Hz, 1H),7.40-7.60(m, 6H), 7.31(d, J=7.69Hz, 1H), 6.89(dd, J=7.14Hz, J=7Hz, 1H),6.71-6.79 (m, 2H), 6.55(dd, J=7.1Hz, J=7Hz, 1H), 5.20(s, 2H), 4.93(bs,2H). 4 45  59

CH CH H N-(2-aminophenyl)-3- {4-[(3,4,5-trimethoxy-benzylamino)-methyl]- phenyl}-acrylamide ¹H-NMR(CDCl₃), δ(ppm): 8.25(bs,1H), 7.59(d, J=15.6Hz, 1H), 7.38(d, J=7.5Hz, 2H), 7.29(d, J=7.5Hz, 2H),7.25(m, 1H), 7.02(t, J=6.8Hz, 1H), 6.75(m, 2H), 6.62 (d, J=15.6Hz, 1H),6.58(s, 2H), 3.97(bs, 3H), 3.80(s, 9H), 3.78(s, 2H), 3.72(s, 2H). 5 46 61b

N CH Me N-(2-aminophenyl)-3-[6- (4-methoxy- benzylamino)-pyridin-3-yl]-2-methyl-acrylamide ¹H-NMR(DMSO-d6), δ(ppm): 9.15(bs, 1H), 8.13(bs,1H), 7.58(d, J=1.9Hz, 1H), 7.30(m, 4H), 7.12(d, J=7.7Hz, 1H), 6.91 (m,3H), 6.75(d, J=7.8Hz, 1H), 6.57(m, 2H), 4.83(bs, 2H), 4.43(d, J=5.5Hz,2H), 3.72(s, 3H), 3.33(s, 3H). 3 47  65

CH CH H N-(2-amino-phenyl)-3- [4-(4-methoxy- benzylamino)-phenyl]-acrylamide ¹H NMR:(DMSO-d6)δ(ppm): 9.15(s, 1H), 7.24-7.38(m, 6H),6.84-6.90(m, 3H), 6.72 (m, 2H), 6.49-6.60(m, 4H), 4.84(s, 2H), 4.22(d,J=5.77Hz, 2H). 6 48  71

CH CH H N-(2-Amino-phenyl)-3- (4-styrylamino-phenyl)- acrylamide ¹HNMR:(DMSO-d₆)δ(ppm): 9.22(bs, 1H), 7.45(d, J=6.9Hz, 2H), 7.39(d, J=9.0Hz, 2H), 7.34(d, J=7.4Hz, 2H), 7.26(dt, J=7.4Hz, 6.8Hz, 2H), 6.93(dt,J=7.9 Hz, 7.1Hz, 1H), 6.78(d, J=7.9Hz, 1H), 6.69 (d, J=8.5Hz, 2H),6.63-6.55(m, 4H), 6.44-6.37(m, 1H), 4.95(bs, 2H), 3.95(bs, 2H). 7 49  72

CH CH H N-{4-[2-(2-Amino- phenylcarbamoyl)-vinyl]- phenyl}-4-methoxy-benzamide ¹H NMR:(DMSO-d₆)δ(ppm): 9.4(bs, 1H), 7.60(d, J=8.5Hz, 1H),7.54-7.45(m, 3H), 7.87(d, J=7.7Hz, 1H), 7.10(d, J=8.8 Hz, 1H),6.95-6.77(m, 3H), 6.62(d, J=7.7Hz, 2H), 6.08-6.04(m, 2H), 4.98(bs, 2H),3.72 (s, 3H). 7 50  76

N CH H N-(2-aminophenyl)-3- {6-[2-(4-oxo-4H- quinazolin-3-yl)-ethylamino]-pyridin-3- yl}-acrylamide ¹H-NMR(DMSO-d6), δ(ppm): 9.24(bs,1H), 8.17(dd, J=8.0Hz, 1.6Hz, 1H), 8.11 (bs, 1H), 8.08(d, J=1.9Hz, 1H),7.82(dt, J=8.5Hz, 1.4Hz, 1H), 7.64(d, J=8.2Hz, 2H), 7.25(t, J=5.8Hz,1H), 6.90(dt, J=15.7 Hz, 1H), 6.74(dd, J=8.0Hz, 1.4Hz, 1H), 6.58(m, 3H),4.95(bs, 2H), 4.17(t, J=5.2 Hz, 2H), 3.68(m, J=5.2Hz, 2H). 8 51  78

N CH H N-(2-aminophenyl)-3- {6-[2-(4-benzyl-2,6- dioxo-piperazin-1-yl)-ethylamino]-pyridin-3- yl}-acrylamide ¹H-NMR(CD₃OD-d4), δ(ppm): 8.09(d,J=1.8Hz, 1H), 7.68(dd, J=8.7Hz, 2.1Hz, 1H), 7.53(d, J=15.6Hz, 1H),7.29(m, 6H), 7.20(dd, J=7.8Hz, 1.2Hz, 1H), 7.02(dt, J=9.0Hz, 1.2Hz, 1H),6.86(dd, J=8.1Hz, 1.2Hz, 1H), 6.73(dt, J=7.5Hz, 1.5Hz, 1H), 6.61(d,J=15.6Hz, 1H), 6.50(d, J=8.7 Hz, 1H), 4.85(bs, 3H), 3.97(t, J=7.5Hz,2H), 3.60(s, 2H), 3.57(t, J=7.5Hz, 2H), 3.38(s, 4H). 8 52  83

CH CH H (E)-4-{[4-Amino-6-(2- indanyl-amino)- [1,3,5]triazin-2-ylamino]-methyl}-N-(2-amino- phenyl)-cinamide ¹H NMR(300 MHz, acetone-d₆)δ(ppm):8.87(bs, 1H), 7.69(d, J=15.7Hz, 1H), 7.59 (bd, J=7.7Hz, 2H), 7.49-7.34(m, 3H), 7.28-7.11(m, 4H), 7.05-6.91(m, 2H), 6.88 (dd, J=8.0, 1.4Hz,1H), 6.69(td, J=7.6, 1.4 Hz, 1H), 6.65-5.50(m, 4H), 4.83-4.53(m, 5H),3.34-3.11(m, 2H), 2.98-2.80(m, 2H). 9 55  89

N CH H N-(2-aminophenyl)-3-[6- (4-methoxy- benzylamino)-pyridin-3-yl]-acrylamide ¹H-NMR(DMS0-d6), δ(ppm): 9.24(bs, 1H), 8.19(d, J=1.6Hz,1H), 7.64(d, J=8.5 Hz, 1H), 7.52(t, J=5.5Hz, 1H), 7.42(d, J=15.7Hz, 1H),7.32(d, J=7.4Hz, 1H), 7.26 (d, J=8.5Hz, 2H), 6.90(m, 1H), 6.88(dd,J=8.5Hz, 2H), 6.74(d, J=6.9Hz, 1H), 6.58 (m, 3H), 4.92(bs, 2H), 4.45(d,J=5.5Hz, 2H), 3.72(s, 3H). 3 56  90

N CH H N-(2-aminophenyl)-3-{6- [(pyridin-3-ylmethyl)- amino]-pyridin-3-yl}-acrylamide ¹H-NMR(CD₃OD-d4), δ(ppm): 8.47(bs, 1H), 8.33(bs, 1H),8.02(m, 1H), 7.73(m, 1H), 7.61(d, J=8.5Hz, 1H), 7.46(d, J=15.4 Hz, 1H),7.29(m, 1H), 7.14(d, J=7.7Hz, 1H), 6.94(d, J=7.4Hz, 1H), 6.80(d, J=7.9Hz, 1H), 6.66(t, J=7.9Hz, 1H), 6.53(m, 2H), 4.54(m, 2H), 3.59(bs, 2H). 357  91

N CH H N-(2-aminophenyl)-3-{6- [(pyridin-4-ylmethyl)-amino]-pyridin-3-yl}- acrylamide ¹H-NMR(DMSO-d6), δ(ppm): 9.27(bs, 1H),8.48(dd, J=1.6Hz, 4.4, 1H), 8.16(d, J=1.6Hz, 1H), 7.70(m, 2H), 7.42(d,J=15.6 Hz, 1H), 7.31 (m 3H), 6.90(t, J=6.9Hz, 1H), 6.73(d, J=6.9Hz, 1H),6.58(m, 4H), 4.98(bs, 2H), 4.57(d, J=6.0Hz, 2H). 3 58  92

N CH H N-(2-aminophenyl)-3-[6- (4-fluoro-benzylamino)-pyridin-3-yl]-acrylamide ¹H-NMR(DMSO-d6), δ(ppm): 9.24(bs, 1H), 8.18(d,J=1.6Hz, 1H), 7.65(dd, J=8.8 Hz, 0.8Hz, 1H), 7.60(t, J=5.8Hz, 1H),7.42(d, J=15.7Hz, 1H), 7.36(m, 3H), 7.13 (t, J=8.8Hz, 2H), 6.90(t,J=7.4Hz, 1H), 6.73(dd, J=6.9Hz, 1.0Hz, 1H), 6.58(m, 3H), 4.91(bs, 2H),4.50(d, J=6.0Hz, 2H). 3 59  93

N CH H N-(2-aminophenyl)-3-(6- benzylamino-pyridin-3- yl)-acrylamide¹H-NMR(DMSO-d6), δ(ppm): 9.24(bs, 1H), 8.17(d, J=1.9Hz, 1H), 7.65(dd,J=8.8 Hz, 1.6Hz, 1H), 7.60(t, J=6.0Hz, 1H), 7.41(d, J=15.7Hz, 1H),7.31(m, 5H), 7.23 (m, 1H), 6.89(dt, J=8.0Hz, 1.6Hz, 1H), 6.73(dd,J=8.0Hz, 1.5Hz, 1H), 6.58(m, 3H), 4.92(bs, 2H), 4.53(d, J=6.0Hz, 2H) 360  94

N CH H N-(2-aminophenyl)-3-[6- (3-phenyl-propylamino)-pyridin-3-yl]-acrylamide ¹H-NMR(DMSO-d6), δ(ppm): 9.22(bs, 1H), 8.18(ds,1H), 7.63(d, J=8.8Hz, 1H), 7.42(d, J=15.4Hz, 1H), 7.22(m 7H), 6.90 (t,J=7.7Hz, 1H), 6.75 (d, J=8.0Hz, 1H), 6.57(m 3H), 4.92(bs, 2H), 3.29(dt,J=7.7 Hz, 6.0Hz, 2H), 2.66(t, J=7.7Hz, 2H), 1.84(m, J=7.7Hz, 2H). 3 61 95

N CH H N-(2-aminophenyl)-3-{6- [2-(4-methoxy-phenyl)-ethylamino]-pyridin-3- yl}-acrylamide ¹H-NMR(DMSO-d6), δ(ppm): 9.22(bs,1H), 8.19(bs, 1H), 7.62(d, J=8.5Hz, 1H), 7.42(d, J=15.7Hz, 1H), 7.32(d,J=7.8Hz, 1H), 7.16 (d, J=7.8Hz, 2H), 7.13(m, 1H), 6.91(m, 1H), 6.85(d,J=7.9Hz, 1H), 6.74 (d, J=7.8Hz, 1H), 6.57(m 3H), 4.92(bs, 2H), 3.71(s,3H), 3.47(dd, J=7.3Hz, 6.0 Hz, 2H), 2.78(t, J=7.3Hz, 2H). 3 62  96

N CH H N-(2-aminophenyl)-3-[6- (4-dimethylamino- benzylamino)-pyridin-3-yl]-acrylamide ¹H-NMR(DMSO-d6), δ(ppm): 9.23(bs, 1H), 8.18(bs, 1H),7.63(d, J=8.2Hz, 1H), 7.41(m, 2H), 7.31(d, J=7.4Hz, 1H), 7.15 (d,J=8.5Hz, 2H), 6.90 (t, J=7.4Hz, 1H), 6.74(d, J=7.0Hz, 1H), 6.68(d,J=8.5Hz, 2H), 6.58(m, 3H), 4.91(bs, 2H), 4.39(d, J=5.5Hz, 2H), (bs, 2H).3 63  97

N CH H N-(2-aminophenyl)-3-[6- (3-imidazol-1-yl- propylamino)-pyridin-3-yl]-acrylamide ¹H-NMR(CD₃OD-d4), δ(ppm): 8.09(bs, 1H), 8.05(d, J=1.9Hz,1H), 7.67(m, 2H), 7.49(d, J=15.7Hz, 1H), 7.28(m, 2H), 7.17 (m, 2H),6.98(dt, J=13.7 Hz, 7.7Hz, 1H), 6.83(dd, J=8.0Hz, 1.1Hz, 1H), 6.69(dt,J=9.1Hz, 1.4Hz, 1H), 6.58(d, J=15.7Hz, 1H), 6.51(d, J=8.8Hz, 1H),4.15(t, J=7.1 Hz, 2H), 3.29(m, 2H), 2.08(m, J=6.9 Hz, 2H). 3 64  98

N CH H N-(2-aminophenyl)-3-[6- (3-trifluoromethoxy-benzylamino)-pyridin-3- yl]-acrylamide ¹H-NMR(acetone-d6), δ(ppm):8.75(bs, 1H), 8.23(d, J=1.9Hz, 1H), 7.69(d, J=8.2 Hz, 1H), 7.55(d,J=15.4Hz, 1H), 7.43(m, 2H), 7.34(bs, 2H), 7.19(d, J=6.6Hz, 1H), 6.93(m,2H), 6.83(dd, J=8.0Hz, 1.4Hz, 1H), 6.67(m, 3H), 4.71(d, J=6.3Hz, 2H),4.65(bs, 2H). 3 65  99

N CH H N-(2-aminophenyl)-3-[6- (4-trifluoromethoxy-benzylamino)-pyridin-3- yl]-acrylamide ¹H-NMR(acetone-d6), δ(ppm):8.81(bs, 1H), 8.21(d, J=1.9Hz, 1H), 7.66(d, J=7.4 Hz, 1H), 7.56(d,J=15.7Hz, 2H), 7.49(d, 2H), J=8.2Hz, 1H), 7.34(d, J=8.1Hz, 1H), 7.25(t,J=8.0Hz, 1H), 6.93(m, 2H), 6.73 (m, 3H), 4.67(d, J=6.0Hz, 2H), 4.66(bs,2H). 3 66 100

N CH H N-(2-aminophenyl)-3-[6- (3,5-difluoro- benzylamino)-pyridin-3-yl]-acrylamide ¹H-NMR(DMSO-d6), δ(ppm): 9.25(bs, 1H), 8.18(d, J=2.2Hz,1H), 7.67(m, 2H), 7.42(d, J=15.7Hz, 1H), 7.31(d, J=7.7Hz, 1H), 7.08(dt,J=9.3Hz, 2.2Hz, 1H), 7.03 (dd, J=8.8Hz, 1.9Hz, 2H), 6.90(dt, J=7.3 Hz,1.4Hz, 1H), 6.73(dd, J=8.0Hz, 1.4 Hz, 1H), 6.60(m 3H), 4.92(bs, 2H),4.56 (d, J=6.0Hz, 2H). 3 67 101

N CH H N-(2-aminophenyl)-3-[6- (3-trifluoromethyl-benzylamino)-pyridin-3- yl]-acrylamide ¹H-NMR(DMSO-d6), δ(ppm): 9.25(bs,1H), 8.14(bs, 1H), 7.86(m, 6H), 7.42(d, J=15.6Hz, 1H), 7.31(d, J=7.4Hz,1H), 6.90 (dt, J=8.8Hz, 1.1Hz, 1H), 6.74(dd, J=8.0 Hz, 1.4Hz, 1H),6.60(m 3H), 4.96(bs, 2H), 4.63(d, J=5.8Hz, 2H). 3 68 102

N CH H 3-[6-(3-aminomethyl- benzylamino)-pyridin-3-yl]-N-(2-aminophenyl)- acrylamide ¹H-NMR(DMSO-d6), δ(ppm): 9.28(bs, 1H),8.17(bs, 1H), 7.66(d, J=5.8Hz, 2H), 7.37(m, 6H), 6.88(dd, J=8.0Hz,0.9Hz, 1H), 6.73(dd, J=8.0Hz, 0.9Hz, 1H), 6.59 (m, 3H), 4.55(d, J=5.8Hz,2H), 3.96(s, 2H), 3.37(bs, 4H). 3 70 104

CH CH H {4-[2-(2-amino-phenyl- carbamoyl)-vinyl]- benzyl}-carbamic acidpyridin-3-yl methyl ester ¹H NMR:(DMSO-d6)δ(ppm): 9.36(s, 1H), 8.57(s,1H), 8.51(d, J=4.6Hz, 1H), 7.91 (m, 1H), 7.77(d, J=7.68Hz, 1H),7.28-7.57 (m, 7H), 6.88 (dd, J=15.66Hz, 4.40Hz, 2H), 6.73(m, 1H),6.56(m, 1H), 5.01(s, 2H), 4.93(bs, 2H), 4.10(d, J=6.04Hz, 2H). 4 71 105

CH CH H (2-{4-[2-(2-amino- phenylcarbamoyl)-vinyl]-phenyl}-ethyl)-carbamic acid pyridin-3-yl methyl ester ¹HNMR:(DMSO-d6)δ(ppm): 9.34(s, 1H), 8.52(m, 2H), 7.71(d, J=7.69Hz, 1H),7.20-7.60(m, 8H), 6.87(m, 2H), 6.73(m, 1H), 6.56 (m, 1H), 5.03(s, 2H),4.92(s, 2H), 3.30(m, 2H), 2.75(m, 2H). 4 72 106

CH CH H N-(2-aminophenyl)-3-{4- [(3,4,5-trimethoxy-phenylamino)-methyl]- phenyl}-acrylamide ¹H-NMR(acetone-d6), δ(ppm):8.49(bs, 1H), 8.41(d, J=7Hz, 1H), 7.63(d, J=15.6 Hz, 1H), 7.56(d, J=8Hz,2H), 7.45 (d, J=8 Hz, 2H), 7.07(m, 2H), 6.90(d, J=15.6Hz, 1H), 6.76(m,1H), 6.74(m, 1H), 5.99(s, 2H), 4.36(s, 2H), 3.69(s, 6H), 3.68(bs, 2H),3.67(s, 3H). 5 73 107

CH CH H N-(2-aminophenyl)-3-(4- {[(3,4,5-trimethoxy-benzyl)-amino]-methyl}- pheyl)-acrylamide ¹H-NMR(CDCl₃), δ(ppm):7.70(bs, 1H), 7.43(d, J=7.4Hz, 1H), 7.33(d, J=4.9Hz, 2H), 7.26(d,J=4.9Hz, 2H), 7.25(m, 1H), 7.03(t, J=7.4Hz, 1H), 6.78(d, J=7.4Hz, 1H),6.75(m, 1H), 6.61(s, 2H), 6.57(m, 1H), 4.08(bs, 2H), 3.86(s, 6H),3.83(s, 3H), 3.50(s, 2H), 3.47(s, 2H), 2.21(s, 3H). 5 74 108

CH CH H N-(2-aminophenyl)-3-{4- [(3,4,5-trimethoxy-phenyl)-amino]-methyl}- phenyl}-acrylamide ¹H-NMR(CDCl₃), δ(ppm):7.74(d, J=15.4 Hz, 1H), 7.50(d, J=7.4Hz, 2H), 7.25(m, 3H), 7.06(t,J=1.9Hz, 1H), 6.82(d, J=7.4 Hz, 2H), 6.58(d, J=15.4Hz, 1H), 5.96(s, 2H),4.50(s, 2H), 3.79(s, 6H), 3.78(bs, 2H), 3.77(s, 3H), 3.00(s, 3H). 5 75109

CH CH H N-(2-Amino-phenyl)-3- {4-[(6-methoxy-pyridin-3-ylamino)-methyl]- phenyl}-acrylamide ¹H NMR:(DMSO-d₆)δ(ppm): 9.4(bs,1H), 7.60(d, J=8.5Hz, 1H), 7.54-7.45(m, 3H), 7.87(d, J=7.7Hz, 1H),7.10(d, J=8.8Hz, 1H), 6.95-6.77(m, 3H), 6.62(d, J=7.7Hz, 2H),6.08-6.04(m, 2H), 4.98(bs, 2H), 3.72(s, 3H). 5 76 110

CH CH H N-(2-Amino-phenyl)-3- [4-(quinolin-2-ylsulfanyl-methyl)-phenyl]- acrylamide ¹H NMR:(DMSO-d₆)δ(ppm): 9.41(bs, 1H),8.21(d, J=8.5, 1H), 7.97(dt, J=7.7, 8.8Hz, 2H), 7.78(dt, J=7.1Hz, 8.2Hz,1H), 7.61-7.53(m, 5H), 7.40(dd, J=8.5Hz, 7.6Hz, 2H), 6.97-6.77(m, 4H),6.6(dt, J=7.7Hz, 7.5Hz, 1H), 4.98(bs, 2H), 4.65(bs, 2H). 5 77 111

CH CH H N-(2-amino-phenyl)-3- {4-[(pyridin-3-ylmethyl)- amino]-phenyl}-acrylamide ¹H NMR:(DMSO-d6)δ(ppm): 9.15(s, 1H), 7.24-7.38(m, 6H),6.84-6.90(m, 3H), 6.72 (m, 2H), 6.49-6.60(m, 4H), 4.84(s, 2H), 4.22(d,J=5.77Hz, 2H). 6 78 112

N CH H N-(2-Amino-phenyl)-3- (6-styrylamino-pyridin- 3-yl)-acrylamide ¹HNMR:(DMSO-d₆)δ(ppm): 7.96(d, J=9.1Hz, 2H), 7.55(d, J=14.2Hz, 1H), 7.48(d, J=7.4Hz, 2H), 7.39-7.29(m, 4H), 7.07-6.91(m, 3H), 6.81-6.64(m, 3H),6.47-6.38(m, 1H), 4.21(bs, 2H). 7 79 113

N N H N-(2-amino-phenyl)-3- [2-(4-nitro-benzylamino)- pyrimidin-5-yl]-acrylamide ¹H NMR:(DMSO-d6)δ(ppm): 9.30(s, 1H), 8.58(bs, 2H), 8.36(m,1H), 8.20(m, 2H), 7.58(m, 2H), 7.28-7.42(m, 2H), 6.52-6.92 (m, 4H),4.90(s, 2H), 4.64(d, J=6Hz, 2H). 7 80 114

N CH H N-(5-[2-(2-Amino- phenylcarbamoyl-vinyl)-pyridin-2-yl)-4-methoxy- benzamide ¹H NMR:(DMSO-d₆)δ(ppm): 10.87(bs,1H), 9.45(bs, 1H), 8.66(bs, 1H), 8.33(d, J=7.4Hz, 1H), 8.14-8.08(m, 3H),7.63(d, J=15.6Hz, 1H), 7.40(d, J=7.7Hz, 1H), 7.08 (d, J=6.8Hz, 2H),6.97(d, J=12.3Hz, 2H), 6.80(d, J=7.9Hz, 1H), 6.63(dt, J=7.7Hz, 7.4Hz,1H), 5.06(bs, 2H), 3.88(s, 3H) 7 81 115

N N H 3-[2-(4-amino-benzyl- amino)-pyrimidin-5-yl]- N-(2-amino-phenyl)-acrylamide ¹H NMR:(DMSO-d6)δ(ppm): 9.27(s, 1H), 8.83(s, 2H), 7.97(t,J=6Hz, 1H), 7.37 (d, J=15.9Hz, 1H), 7.29(d, J=7.11Hz, 1H), 6.96(d,J=8.24Hz, 2H), 6.88(m, 1H), 6.70 (m, 2H), 6.55(m, 1H), 6.47(d, J=8.2Hz,2H), 4.90(s, 4H), 4.34(d, J=6.0Hz, 2H). 7 82 116

N CH H N-(2-aminophenyl)-3-[6- (3,4,5-trimethoxy-benzylamino)-pyridin-3- yl]-acrylamide ¹H-NMR(CDCl₃), δ(ppm): 8.38(bs,1H), 7.49(m, 1H), 7.42(dd, J=8.5Hz, 2.2Hz, 1H), 7.41(m, 1H), 7.30(d,J=7.9Hz, 1H), 7.10(bs, 1H), 7.02(t, J=7.4Hz, 1H), 6.75 (d, J=15.0Hz,1H), 6.73(m, 1H), 6.65(m, 2H), 6.36(d, J=8.8Hz, 1H), 6.23(d, J=15.0 Hz,1H), 4.34(s, 2H and bs, 2H), 3.84(s, 3H), 3.81(s, 6H). 7, 3 83 117

N CH H N-(2-Amino-phenyl)-3- [6-(4-methyl- benzylamino)-pyridin-3-yl]-acrylamide ¹H NMR:(DMSO-d₆)δ(ppm): 8.28(bs, 1H), 7.98(d, J=9.6Hz,1H), 7.57(d, J=15.6 Hz, 1H), 7.38(d, J=7.7Hz, 1H), 7.29(d, J=7.9Hz, 2H),7.22(d, J=7.6Hz, 2H), 7.08 (dt, J=8.2Hz, 7.7Hz, 1H), 6.98(d, J=9.1 Hz,2H), 6.87(t, J=8.2Hz, 1H), 6.75(d, J=15.1Hz, 1H), 4.57(s, 2H), 2.53(s,3H). 7 84 118

N N H N-(2-amino-phenyl)-3- [2(4-methoxy- benzylamino)-pyrimidin-5-yl]-acrylamide ¹H NMR:(DMSO-d6)δ(ppm): 9.27(s, 1H), 8.54(s, 2H),8.12(m, 1H), 7.30(m, 4H), 6.53-6.91(m, 6H), 4.90(s, 2H), 4.46(d,J=4.9Hz, 2H), 3.7(s, 3H). 7  84b 118b

N CH H N-(2-Amino-phenyl)-3- [6-(3,4-dimethoxy- phenyl)-pyridin-3-yl]-acrylamide ¹H NMR(20% CD₃OD in CDCl₃):

8.75 (s, 1H), 7.95 (m, 1H), 7.74-7.59(m, 3H), 7.50(m, 1H), 7.24(d,J=7.8Hz, 1H), 7.07 (m, 1H), 6.95(d, J=8.4Hz, 1H), 6.89-6.83 (m, 3H),3.96(s, 3H), 3.91(s, 3H). 9, 15

TABLE 3b

Ex. Cpd. n Name Characterization Scheme 53 87 0 2-(4-methoxy-¹H-NMR(DMSO-d6), δ(ppm): 9.66(bs, 1H), 8.32(s, 1H), 8.05(d, J=8.8Hz, 10benzylamino)-quinoline- 1H), 7.96(dd, J=9.1Hz, 2.2Hz, 1H), 7.72(d,J=2.2Hz, 1H), 7.55(dd, J=8.5 6-carboxylic acid(2- Hz, 2.2Hz, 1H),7.34(dd, J=8.5Hz, 2.2Hz, 1H), 7.20(d, J=7.7Hz, 1H), 6.97aminophenyl)-amide (t, J=7.7Hz, 1H), 6.90(m 2H), 6.80(d, J=7.9Hz, 1H),6.61(t, J=6.3Hz, 1H), 4.90(bs 2H), 4.58(d, J=3.3Hz, 2H), 3.73(s, 3H),3.33(bs, 1H). 54 88 1 N-(2-aminophenyl)-3-[2- ¹H-NMR(DMSO-d6), δ(ppm):9.70(bs, 1H), 9.40(bs, 1H), 8.20(d, J=8.9Hz, 10 (4-methoxy- 1H),8.03(bs, 2H), 7.94(d, J=7.2Hz, 1H), 7.64(dd, J=15.7Hz, 2.5Hz, 1H),benzylamino)-quinolin-6- 7.41(d, J=8.5Hz, 2H), 7.39(m, 1H), 7.14(d,J=8.9Hz, 1H), 7.05(d, J=15.7 yl]-acrylamide Hz, 1H), 6.97(m, 1H),6.95(d, J=8.5Hz, 2H), 6.81(d, J=8.0Hz, 1H), 6.65(t, J=7.2Hz, 1H),4.76(s, 2H), 3.75(s, 3H).

TABLE 3c

Ex. Cpd. Name Characterization Scheme 43 51N-(2-aminophenyl)-3-[6-(4-methoxy- ¹H-NMR(CDCl₃), δ(ppm): 7.60(bs, 1H),7.55(bs, 1H), 7.43(t, J=7.7 3 benzylamino)-pyridin-2-yl]-acrylamide Hz,1H), 7.29(d, J=8.3Hz, 2H), 7.17(d, J=15.1Hz, 1H), 7.06(t, J= 7.7Hz, 1H),6.88(d, J=8.3Hz, 2H), 6.80(m, 2H), 6.70(m, 3H), 6.41 (d, J=8.5Hz, 1H),4.50(d, J=5.5Hz, 2H), 3.80(s, 3H), 3.45(bs, 2H).

TABLE 3d

Ex. Cpd W Y Z R Name Characterization Schm 347 492

CH CH H N-(2-Amino-phenyl)-3- {4-[(4,6-dimethoxy- pyrimidin-2-ylamino)-methyl]-phenyl}- acrylamide ¹H-NMR(DMSO-d6), δ(ppm): 9.36(bs, 1H),7.55(d, J= 7.4Hz, 2H), 7.48(s, 1H), 7.38(d, J=7.9Hz, 2H), 7.33(dJ=7.9Hz, 1H), 6.91(m, 2H), 6.73(d, J=8.2Hz, 1H), 6.56 (dd, J=7.4, 7.7Hz,1H), 5.35(s, 1H), 4.93(bs, 2H), 4.46 (dd, J=6.04 2H), 3.32(s, 6H) 3, 7348 493

CH CH H N-(2-Amino-phenyl)-3- {4-[(4-chloro-6- methoxy-pyrimidin-2-ylamino)-methyl]- phenyl}-acrylamide ¹H-NMR(DMSO-d6), δ(ppm): 9.37(bs,1H), 7.58-7.50 (m, 3H), 7.37-7.32(m, 3H), 6.94-6.83(m, 2H), 6.75(dJ=8.0Hz, 1H), 6.57(t, J=7.5, 1H), 6.13(bs, 1H), 4.94 (bs, 2H), 4.48(d,J=6.0, 2H), 3.84(s, 3H) 3, 7 349 494

CH CH H N-(2-Amino-phenyl)-3- [4-(3,5-dimethoxy- benzylamino)-phenyl]-acrylamide ¹H-NMR(DMSO-d6), δ(ppm): 9.38(bs, 1H), 7.55-7.40 (m, 6H),6.88-6.57(m, 3H), 6.35-6.32(m, 1H), 5.73(m, 3H), 4.94(s, 2H), 4.26(s,2H), 3.63(s, 6H). 3, 7 350 495

CH CH H N-(2-Amino-phenyl)-3- [4-(3,5-dinitro- benzylamino)-phenyl]-acrylamide ¹H-NMR(DMSO-d6), δ(ppm): 9.38(bs, 1H), 7.74 (bs, 3H), 7.61(d,J=8.2Hz, 2H), 7.56-7.44(m, 3H), 7.32(d J=8.0Hz, 1H), 6.91-6.85(m, 2H),6.73(d, J=7.9Hz, 1H), 6.66-6.56(m, 1H), 4.93(bs, 2H), 4.52(bs, 2H). 3, 7351 496

CH CH H N-(2-Amino-phenyl)-3- [4-(3-trifluoromethoxy-benzylamino)-phenyl]- acrylamide ¹H-NMR(DMSO-d6), δ(ppm): 9.22(bs, 1H),7.52 (d, J=7.9Hz, 2H), 7.44(bs, 1H), 7.38(bs, 3H), 7.28(d J=6.9Hz, 2H),6.95-6.92(m, 2H), 6.79(d, J=8.2Hz, 1H), 6.69-6.59(m, 3H), 4.95(bs, 2H),4.45(bs, 2H). 58 352 497

CH CH H N-(2-Amino-phenyl)-3- [4-(3,4,5-trimethoxy- phenoxymethyl)-phenyl]-acrylamide ¹H-NMR(DMSO-d6), δ(ppm): 9.45(bs, 1H), 8.01 (bs, 2H),7.78-7.5(m, 4H), 7.49-7.40(m, 1H), 6.98(dd, J=7.0, 8.2Hz, 1H), 6.82(d,J=7.0Hz, 1H), 6.64(dd, J=7.0, 7.6 Hz, 1H), 6.41(bs, 2H), 5.17(s, 2H),3.81(s, 6H), 3.64(s, 3H). 3, 7 353 498

CH CH H N-(2-Amino-phenyl)-3- [4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin- 2-yl)-phenyl]- acrylamide ¹H-NMR(DMSO-d6),δ(ppm): 9.22(bs, 1H), 7.17 (d, J=8.2Hz, 2H), 6.97(d, J=8.2Hz, 2H),6.93(d, J=7.6Hz, 1H), 6.85(bs, 1H), 6.77(bs, 1H), 6.60-6.53(m, 3H),6.43- 6.40(m, 2H), 4.97(bs, 2H), 4.43(bs, 2H), 3.78(s, 3H), 3.77(s, 3H),2.87-2.85(m, 2H), 2.65-2.62(m, 2H). 37 354 499

CH CH H N-(2-Amino-phenyl)-3- (4-{[(1H-indol-2- ylmethyl)-(3,4,5-trimethoxy-phenyl)- amino]-methyl}- phenyl)-acrylamide ¹H-NMR(DMSO-d6),δ(ppm): 10.77(bs, 1H), 9.39 (bs, 1H), 7.62(d, J=7.9Hz, 1H), 7.49(d,J=5.7Hz, 2H), 7.37 (d, J=7.9Hz, 2H), 7.26(d, J=7.9, 2H), 7.10(t,J=7.5Hz, 2H), 7.00-6.83(m, 4H), 6.78(d, J=7.9Hz, 1H), 6.61(t, J=7.5Hz,1H), 5.98(s, 1H), 5.32(bs, 1H), 4.98(bs, 2H), 4.32(d, J=5.2Hz, 2H),3.98(bs, 2H), 3.73(s, 3H), 3.67 (s, 3H), 3.64(s, 3H). 58 355 500

CH CH H N-(2-Amino-phenyl)-3- [4-(3,4,5-trimethoxy-phenylsulfanylmethyl)- phenyl]acrylamide ¹H-NMR(DMSO-d6), δ(ppm):9.69(bs, 1H), 8.04 (d, J=8.3Hz, 2H), 7.78(d, J=8.3Hz, 2H), 7.58-7.55(m,2H), 7.06(d, J=6.2Hz, 1H), 6.96(d, J=7.3Hz, 1H), 6.90(d, J=7.0Hz, 1H),6.60(bs, 1H), 5.81(s, 2H), 4.34(bs, 2H), 3.78(s, 6H), 3.67(s, 3H). 3, 7356 501

CH CH H 3-{4-[(6-Acetyl- benzo[1,3]dioxol-5- ylamino)-methyl]-phenyl}-N-(2-amino- phenyl)-acrylamide ¹H-NMR(DMSO-d6), δ(ppm): 9.81(bs,1H), 7.95 (d, J=7.9Hz, 2H), 7.58(d, J=7.9Hz, 2H), 7.39(bs, 1H), 7.21 (d,J=7.4Hz, 1H), 7.02-7.00(m, 2H), 6.85(d, J=7.5Hz, 1H), 6.64(t, J=7.4Hz,1H), 6.60(bs, 1H), 6.36(bs, 1H), 6.00(d, J=2.2Hz, 2H), 4.60(bs, 2H),2.50(bs, 3H). 58 357 502

CH CH H N-(2-Amino-phenyl)-3- {4-[(5-methoxy- benzothiazol-2-ylamino)-methyl]- phenyl}-acrylamide ¹H-NMR(DMSO-d6), δ(ppm): 9.43(bs,1H), 8.37 (bs, 1H), 7.66-7.57(m, 3H), 7.49(d, J=7.5Hz, 2H), 7.37-7.33(m, 3H), 6.96-6.90(m, 1H), 6.87(d, J=8.8Hz, 1H), 6.80 (d, J=7.9Hz, 1H),6.63(t, J=7.5Hz, 1H), 4.99(bs, 2H), 4.64(bs, 2H), 3.37(s, 3H). 58 358503

CH CH H N-(2-Amino-phenyl)-3- {4-[(4-morpholin-4-yl-phenylamino)-methyl]- phenyl}-acrylamide ¹H-NMR(DMSO-d6), δ(ppm):9.42(bs, 1H), 7.63-7.56 (m, 3H), 7.47(d, J=7.9Hz, 2H), 7.39(d, J=7.5Hz,1H), 6.95(d, J=8.3Hz, 1H), 6.82(bs, 1H), 6.77(d, J=8.4Hz, 2H),6.66-6.56(m, 3H), 5.91(bs, 1H), 5.01(bs, 2H), 4.30 (bs, 2H), 3.74(bs,4H), 2.93(bs, 4H). 58 359 504

CH CH H N-(2-Amino-phenyl)-3- (4-[(4-trifluoromethoxy-phenylamino)-methyl]- phenyl}-acrylamide ¹H-NMR(DMSO-d₆), δ(ppm):9.42(s, 1H), 7.64(d, J= 7.9Hz, 2H), 7.59(d, J=15.9Hz, 1H), 7.48(d, J=8.0Hz, 2H), 7.39(d J=7.4Hz, 1H), 7.10(d, J=8.2Hz, 2H), 6.99(d, J=7.1Hz,1H), 6.92(d, J=15.4Hz, 1H), 6.81 (dd, J=1.3, 8.0Hz, 1H), 6.61-6.68(m,4H), 4.99(s, 2H), 4.36(d, J=6.0Hz, 2H). 3, 33 360 505

CH CH H N-(2-Amino-phenyl)-3- [4-(benzo[1,3]dioxol-5- ylaminomethyl)-phenyl]-acrylamide ¹H-NMR(DMSO-d₆), δ(ppm): 9.42(s, 1H), 7.63(d, J=7.7Hz, 2H), 7.59(d, J=15.4Hz, 1H), 7.47(d, J=8.0 Hz, 2H), 7.40(d,J=7.7Hz, 1H), 6.99(d, J=7.1Hz, 1H), 6.92(d, J=16.2Hz, 1H), 6.81(dd,J=1.4, 8.0Hz, 1H), 6.68(d, J=8.2Hz, 1H), 6.62(dd, J=1.4, 7.7Hz, 1H),6.34(d, J=2.2Hz, 1H), 6.05(m, 2H), 5.87(s, 2H), 4.99 (s, 2H), 4.29(d,J=6.0Hz, 2H). 3, 33 361 506

CH CH H N-(2-Amino-phenyl)-3- {4-[(3-trifluoromethoxy-phenylamino)-methyl]- phenyl}-acrylamide ¹H-NMR(DMSO-d₆), δ(ppm):9.43(s, 1H), 7.57-7.66(m, 3H), 7.48(d, J=7.6Hz, 2H), 7.40(d, J=7.6Hz,1H), 7.20(dd, J=8.2, 8.2Hz, 1H), 6.99(d, J=7.6Hz, 1H), 6.93(d, J=15.2Hz,1H), 6.81(m, 2H), 6.64(m, 2H), 6.49- 6.55(m, 2H), 5.00(s, 2H), 4.38(d,J=5.3Hz, 2H). 3, 33 362 507

CH CH H N-(2-Amino-phenyl)-3- {4-[(3-methoxy- phenylamino)-methyl]-phenyl}-acrylamide ¹H-NMR(DMSO-d₆), δ(ppm): 9.42(s, 1H), 7.63(d, J=7.6Hz, 2H), 7.59(d, J=15.8Hz, 1H), 7.47(d, J=7.6 Hz, 2H), 7.40(d,J=7.6Hz, 1H), 6.90-7.02(m, 3H), 6.81 (d, J=7.6Hz, 1H), 6.64(dd, J=7.0,7.0Hz, 1H), 6.36(m, 1H), 6.24(d, J=8.2Hz, 1H), 6.18(m, 2H), 5.00(s, 2H),4.34(d, J=5.3Hz, 2H), 3.69(s, 3H). 3, 33 363 508

CH CH H N-(2-Amino-phenyl)-3- {4-[(2-methoxy- phenylamino)-methyl]-phenyl)-acrylamide ¹H-NMR(DMSO-d₆), δ(ppm): 9.42(s, 1H), 7.62(d, J=7.0Hz, 2H), 7.58(d, J=15.2Hz, 1H), 7.46(d, J=7.6 Hz, 2H), 7.40(d,J=7.0Hz, 1H), 6.94-7.00(m, 1H), 6.87 (d, J=7.6Hz, 2H), 6.81(d, J=7.6Hz,1H), 6.73(dd, J= 7.6, 7.6Hz, 1H), 6.56-6.66(m, 2H), 6.45(d, J=7.6Hz,1H), 5.68(t, J=5.9Hz, 1H), 4.99(s, 2H), 4.41(d, J=6.4 Hz, 2H), 3.87(s,3H). 3, 33 364 509

CH CH H N-(2-Amino-phenyl)-3- (4-phenylaminomethyl- phenyl)-acrylamide¹H-NMR(DMSO-d₆), δ(ppm): 9.42(s, 1H), 7.63(d, J= 7.9Hz, 2H), 7.59(d,J=15.8Hz, 1H), 7.48(d, J=7.9Hz, 2H), 7.39(d, J=7.5Hz, 1H), 7.10 (2d,J=7.5, 7.5Hz, 2H), 6.99(d, J=7.5Hz, 1H), 6.92(d, J=16.2Hz, 1H), 6.81(d,J=7.5Hz, 1H), 6.55-6.64(m, 4H), 6.32(t, J= 6.0, 1H), 4.99(s, 2H),4.35(d, J=5.7Hz, 2H). 3, 33 365 510

CH CH H N-(2-Amino-phenyl)-3- {4-[(4-isopropyl- phenylamino)-methyl]-phenyl}-acrylamide ¹H-NMR(DMSO-d₆), δ(ppm): 9.42(s, 1H), 7.62(d, J=7.0Hz, 2H), 7.59(d, J=15.8Hz, 1H), 7.47(d, J=8.2 Hz, 2H), 7.40(d,J=7.6Hz, 1H), 6.89-6.99(m, 4H), 6.81 (d, J=7.6Hz, 1H), 6.64(dd, J=7.0,7.6Hz, 1H), 6.56(d, J=8.2Hz, 2H), 6.14(t, J=5.9Hz, 1H), 4.99(s, 2H),4.32 (d, J=5.9Hz, 2H), 2.76(m, 1H), 1.17(d, J=7.0Hz, 6H). 3, 33 366 511

CH CH H N-(2-Amino-phenyl)-3- [4-(biphenyl-4- ylaminomethyl)-phenyl]-acrylamide ¹H-NMR(DMSO-d₆), δ(ppm): 9.43(s 1H) 7.57-7.66(m, 5H),7.40-7.52(m, 7H), 7.27(dd, J=7.0, 7.6Hz, 1H), 6.98 (d, J=7.6Hz, 1H),6.93(d, J=15.2Hz, 1H), 6.81(d, J=8.2Hz, 1H), 6.73(d, J=8.2Hz, 2H),6.64(dd, J=7.6Hz, 1H), 6.56(t, J=5.9 Hz, 1H), 4.99(s, 2H), 4.12(d,J=5.9Hz, 2H). 3, 33 367 512

CH N H N-(2-Amino-phenyl)-3- {6-[(3,4,5-trimethoxy-phenylamino)-methyl]- pyridin-3-yl}-acrylamide ¹H-NMR(DMSO-d₆), δ(ppm):9.50(s, 1H), 8.81(s, 1H), 8.05(d, J=8.2Hz, 1H), 7.64(d, J=15.7Hz, 1H),7.52 (d, J=8.2Hz, 1H), 7.39(d, J=7.4Hz, 1H), 6.96-7.05(m, 2H), 6.81(d,J=8.0Hz, 1H), 6.64(dd, J=7.4, 7.4Hz, 1H), 6.26(m, 1H), 5.96(s, 2H),5.01(s, 2H), 4.43(d, J= 5.5Hz, 2H), 3.72(s, 6H), 3.56(s, 3H). 3, 33 369514

CH CH H N-(2-Amino-phenyl)-3- (4-{[1-(3-benzyl-7- chloro-4-oxo-3,4-dihydro-quinazolin-2- yl)-ethylamino]-methyl}- phenyl)-acrylamide¹H-NMR(DMSO-d₆), δ(ppm): 9.50(s, 1H), 8.28(d, J= 8.4Hz, 1H),7.81-7.72(s, 3H), 7.66(d, J=8.1Hz, 2H), 7.88(d, J=15.6Hz, 1H), 7.50(d,J=8.1Hz, 2H), 7.45- 7.26(m, 4H), 7.24-7.15(m, 2H), 7.00-6.86(m, 2H),6.84 (d, J=8.1Hz, 1H), 6.68(t, J=7.5Hz, 1H), 5.45(d, J= 16.8Hz, 1H),533(d, J=16.8Hz, 1H), 4.62(bs, 1H), 4.25(d, J=12.9Hz, 1H), 4.92(d,J=12.9Hz, 1H), 1.91 (m, 2H), 1.28(m, 1H), 0.90(m, 1H), 0.72(t, J=7.5Hz,3H). 55 371 516 Br— CH CH CH N-(2-Amino-phenyl)-3- (4-bromo-phenyl)-acrylamide ¹H NMR:(Acetone-d₆)δ(ppm): 9.47(bs, 1H), 7.72-7.56 (m, 5H),7.39(d, J=7.4Hz, 1H), 7.00-6.95(m, 2H), 6.81 (d, J=6.9Hz, 1H), 6.64(t,J=7.1Hz, 1H), 5.00(bs, 2H). 14 372 517

CH CH CH N-(2-Amino-phenyl)-4- (2,4,5-trimethoxy- benzylamino)-benzamide¹H NMR:(CD₃OD)δ(ppm): 7.61(d, J=15.4Hz, 1H), 7.44(d, J=8.4Hz, 2H),7.25(d, J=7.5Hz, 1H), 7.10(t, J=7.5 Hz, 1H), 7.00(s, 1H), 6.94(d,J=8.4Hz, 1H), 6.81(t, J=7.0Hz, 1H), 6.76(s, 1H) 6.70(d, J=8.4Hz, 2H),6.92(d, J=15.4Hz, 1H), 4.35(s, 2H), 3.94(s, 3H), 3.92(s, 3H), 3.77(s,3H). 1, 7, 10 373 518

CH CH CH 4-(2-Amino-phenyl)-3- {4-[1-(3,4,5-trimethoxy-phenylamino)-ethyl]- phenyl}-acrylamide 1H NMR(DMSO-d6)δ(ppm): 9.24(s,1H), 8.00 1(d, J=12Hz, 1H); 7.80(d, J=12Hz, 1H), 7.40-7.70(m, 7H),6.80-7.00(m, 2H), 6.70(d, J=12Hz, 1H), 6.20(s, 2H), 4.50(m, 1H), 3.70(s,6H), 3.50(s, 3H), 1.50(d, 3H). 58 374 519

C CH H N-(2-Amino-phenyl)-3- (9H-fluoren-2-yl)- acrylamide ¹H NMR(300MHz, DMSO-d₆)δ(ppm): 9.41(s, 1H), 8.00(t, J=7.9Hz, 2H), 7.88(s, 1H),7.77-7.56(m, 3H), 7.52-7.32(m, 3H), 7.00(d, J=15.8Hz, 1H), 6.96(t, J=7.5Hz, 1H), 6.80(d, J=7.9Hz, 1H), 6.63(t, J=7.5Hz, 1H), 5.00(s, 2H),4.03(s, 2H). 59 375 520

CH CH H N-(2-Amino-phenyl)-4- [2-(2-amino- phenylcarbamoyl)-vinyl]-benzamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.71(s, 1H), 9.43(s,1H), AB system(δ_(A)=8.05, δ_(B)=7.75, J=7.9Hz, 4H), 7.62(d, J=15.8Hz,1H), 7.36(d, J=7.9Hz, 1H), 7.18(d, J=7.5Hz, 1H), 7.05-6.88(m, 3H),6.78(t, J= 7.9Hz, 2H), 6.65-6.55(m, 2H), 4.96 and 4.92(2s, 4H). 59 376521

N CH H N-(2-Amino-phenyl)-3- {6-[2-(pyrimidin-2- ylamino)-ethylamino]-pyridin-3-yl}- acrylamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.29(s, 1H),8.32(d, J=4.9Hz, 2H), 8.24(d, J=1.9 Hz, 1H), 7.71(d, J=6.9Hz, 1H),7.48(d, J=15.7Hz, 1H), 7.38(d, J=7.7 Hz, 1H), 7.26(bs, 2H), 6.96(t,J=6.9Hz, 1H), 6.80(dd, J= 1.1, 7.7Hz, 1H), 6.69-6.61(m, 4H), 5.00(s,2H), 3.52(bs, 4H), 3 377 522

N CH H N-(2-Amino-phenyl)-3- {6-[2-(thiazol-2- ylamino)-ethylamino]-pyridin-3-yl}-acrylamide ¹H NMR(300 MHz, CD₃OD)δ(ppm): 8.12(s, 1H), 8.08(s, 1H), 7.78(d, J=8.8Hz, 1H), 7.54(d, J=15.4Hz, 1H), 7.19(d, J=8.0Hz,1H), 7.04(t, J=7.4Hz, 1H), 6.87(d, J=8.0Hz, 1H), 6.75(t, J=7.4Hz, 1H),6.64(d, J=15.4Hz, 1H), 6.65(s, 1H), 4.90(s, 5H), 3.50-3.45(m, 4H),3.30(d, J=1.3Hz, 1H). 3 378 523

CH CH H N-(2-Amino-phenyl)-3- (4-{[(2-morpholin-4-yl- ethyl)-(3,4,5-trimethoxy-phenyl)- amino]-methyl}- phenyl)-acrylamide ¹H-NMR(CD₃OD),δ(ppm): 7.83(d, J=15.6Hz, 1H), 7.67(d, J=7.8Hz, 2H), 7.62-7.58 (m, 2H),7.53-7.51(m, 2H), 7.49(d, J=7.8Hz, 2H), 7.01(d, J=15.6Hz, 1H), ),4.99(bs, 9H), 4.84(bs, 2H), 4.22(t, J=6.5Hz, 2H), 4.05 (s, 4H), 3.85(s,6H), 3.76(s, 3H), 3.57-3.50(m, 4H). 3, 33, 57 379 524

N CH H N-(2-Amino-phenyl)-3- [6-(3-hydroxy- benzylamino)-pyridin-3-yl]-acrylamide ¹H-NMR(DMSO-d₆), δ(ppm): 9.32(s, 1H), 9.26(s, 1H),8.19(s, 1H), 7.66(d, J=8.5Hz, 1H), 7.57(t, J=6.0Hz, 1H), 7.41(d,J=15.7Hz, 1H), 7.32(d J=7.7Hz), 7.10(t, J=7.6Hz, 1H), 6.91(t, J=7.6Hz,1H), 6.75(m, 3H), 6.59 (m, 4H), 4.98(bs, 2H), 4.46(d, J=5.8Hz, 2H). 3380 525

N CH H N-(2-Amino-phenyl)-3- {6-[3-(2,2,2-trifluoro-ethoxy)-benzylamino]- pyridin-3-yl]- acrylamide ¹H-NMR(DMSO-d₆), δ(ppm):9.25(s, 1H), 8.18(s, 1H), 7.67(d, J=8.8Hz, 1H), 7.59(t, J=6.0Hz, 1H),7.42(d, J=15.7Hz, 1H), 7.30(m, 2H), 7.00(m, 2H), 6.92(m, 2H), 6.74(d,J=8.0Hz, 1H), 6.60(m, 3H), 4.92(s, 2H), 4.73(q, J=8.8Hz, 2H), 4.52(d,J=5.8Hz, 2H). 3 381 526

CH CH H N-(2-Amino-phenyl)-3- (4-{[3-hydroxy-4-(4-methyl-piperazin-1-yl)- phenylamino]-methyl}- phenyl)-acrylamide¹H-NMR(CD₃OD), δ(ppm): 7.64(d, J=15.6Hz, 1H), 7.56(d, J=8.0Hz, 2H), 7.49(m, 1H), 7.40(d, J=8.0 Hz, 2H), 7.21(m, 2H), 7.03(t, J=7.6Hz, 1H),6.88-6.71 (m, 4H), 4.88(bs, 4H), 4.34(s, 2H), 2.86(t, J=4.1Hz, 4H),2.67(bs, 4H), 2.41(s, 3H). 3, 33, 58 382 527

CH CH H N-(2-Amino-phenyl)-3- (4-{[3-fluoro-4-(4-methyl-piperazin-1-yl)- phenylamino]-methyl}- phenyl)-acrylamide¹H-NMR(DMSO-d₆, δ(ppm): 9.43(s, 1H), 7.61(d, J= 8.0Hz, 2H), 7.45(d,J=8.0Hz, 2H), 7.38(d, J=7.6Hz, 1H), 7.00-6.88(m, 2H), 6.85-6.79(m, 2H),6.63(t, J=7.6 Hz, 1H), 6.44-6.30(m, 3H), 4.99(bs, 2H), 4.30(d, J=5.5 Hz,2H), 2.87(bs, 4H), 2.55(m, 4H), 2.27(s, 3H). 3, 33, 58 383 528

CH CH H N-(2-Amino-phenyl)-3- {4-[(3-hydroxy- phenylamino)-methyl]-phenyl}-acrylamide ¹H-NMR(CDCl₃), δ(ppm): 7.49(d, J=14.0Hz, 1H); 7.32(d, J=7.2Hz, 2H), 7.15(d, J=7.2Hz, 2H), 7.05(m, 1H), 6.96(m, 1H),6.90(m, 3H), 6.76(m, 1H), 6.55(d, J=14.0Hz, 1H), 6.03 (m, 1H), 5.99(m,1H), 4.30(bs, 5H), 4.10(s, 2H). 3, 33 384 529

CH CH H N-(2-Amino-phenyl)-3- {4-[(4-trifluoromethyl-pyrimidin-2-ylamino)- methyl]-phenyl}- acrylamide ¹H-NMR(CD₃OD), δ(ppm):7.73(d, J=16.0Hz, 1H); 7.63(d, J=8.5Hz, 1H), 7.58(d, J=8.0Hz, 2H),7.46(d, J=8.0Hz, 2H), 7.38(d, J=8.5Hz, 1H), 7.20(d, J=8.0 Hz, 1H),7.03(dt, J=7.7, 1.4Hz, 1H), 6.89(d, J=1.1Hz, 1H), 6.85(m, 1H), 6.73(dt,J=7.7, 1.1Hz, 1H), 6.56(d, J=16.0Hz, 1H), 5.27(s, 2H), 4.87(bs, 2H),4.62(s, 2H). 3, 33 385 530

CH CH H N-(2-Amino-phenyl)-3- {4-[(3-hydroxymethyl-phenylamino)-methyl]- phenyl}-acrylamide ¹H-NMR(DMSO-d₆), δ(ppm):9.90(s, 1H), 7.58(m, 3H), 7.43(d, J=8.0Hz, 2H); 7.37 (d, J=8.0Hz, 1H),7.11 (m, 1H), 7.00(m, 3H), 6.85(d, J=15.4Hz, 1H), 6.63(s, 1H), 6.51(d,J=7.4,Hz, 1H), 6.46(d, J=7.7Hz, 1H), 4.35(s, 2H), 4.32(s, 2H). 3, 33 386531

CH CH H N-(2-Amino-phenyl)-3- {4-[(4-pyridin-4- ylmethyl-phenylamino)-methyl]-phenyl}- acrylamide ¹H-NMR(DMSO-d₆), δ(ppm): 9.66(s, 1H),8.46(d, J= 4.7Hz, 2H); 7.55(d, J=8.0Hz, 2H), 7.50(d, J=15.7 Hz, 1H),7.39(d, J=8.0Hz, 2H), 7.28(d, J=4.7Hz, 2H), 7.00(d, J=15.7Hz, 1H),6.92(d, J=6.9Hz, 2H), 6.90 (m, 1H), 6.75(d, J=8Hz, 1H), 6.58(m, 2H),6.52(d, J= 6.9,Hz, 2H), 6.10(bs, 1H), 4.26(bs, 2H), 3.80(s, 2H), 2.08(d,J=1.9Hz, 2H). 3, 33 387 532

CH CH H N-(2-Amino-phenyl)-3- {4-[(3-cyano- phenylamino)-methyl]-phenyl}-acrylamide ¹H-NMR(DMSO-d₆), δ(ppm): 9.38(s, 1H), 7.58(d, J=7.7Hz, 2H); 7.54(d, J=15.9Hz, 1H), 7.41 (d, J=7.7Hz, 2H), 7.33(d,J=8.0Hz, 1H), 7.24(t, J=7.7Hz, 1H), 6.92-6.83(m, 5H), 6.75(d, J=8.0Hz,1H), 6.58(t, J= 7.4Hz, 1H), 4.95(bs, 2H), 4.34(d, J=5.8Hz, 2H). 3, 33388 533

CH CH H 3-(4-{[3-(Acetylamino- methyl)-phenylamino]-methyl}-phenyl)-N-(2- amino-phenyl)-acrylamide ¹H-NMR(DMSO-d₆), δ(ppm):9.37(bs, 1H), 8.21(t, J= 5.8Hz, 1H), 7.56(d, J=7.7Hz, 2H), 7.53(d,J=15.7Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.33(d, J=7.1Hz, 1H), 6.97(m,1H), 6.85 (d, J=15.7Hz, 1H), 6.74(dd, J=1.4, 8.0Hz, 1H), 6.58(dt, J=1.4,8.0Hz, 1H), 6.50(bs, 1H), 6.41(d, J=8.0Hz, 2H), 6.30(t, J=6.0 Hz, 1H),4.94(bs, 2H), 4.28(d, J=6.0Hz, 2H), 4.09(d, J=6.0 Hz, 2H), 1.83(s, 3H).3, 33 389 534

CH CH H N-(2-Amino-phenyl)-3- {4-[(4-nitro-3- trifluoromethyl-phenylamino)-methyl]- phenyl}-acrylamide ¹H-NMR(DMSO-d₆), δ(ppm):9.37(bs, 1H), 7.56(d, J= 8.0Hz, 2H), 7.53(d, J=15.7Hz, 1H), 7.41 (d,J=8.0Hz, 2H), 7.33(d, J=7.7Hz, 1H), 6.92(d, J=7.7Hz, 2H), 6.85(d,J=15.7Hz, 1H), 6.74(d, J=8.0Hz, 1H), 6.67- 6.55(m, 4H), 5.84(t, J=5.8Hz,1H), 4.94(bs, 2H), 4.22 (d, J=5.8Hz, 2H). 3, 33 390 535

CH CH H N-(2-Amino-phenyl)-3- {4-[(3,5-dichloro- phenylamino)-methyl]-phenyl)-acrylamide ¹H-NMR(DMSO-d₆), δ(ppm): 9.39(bs, 1H), 7.60(d, J=8.0Hz, 2H), 7.54(d, J=15.7Hz, 1H), 7.40 (d, J=8.0Hz 2H), 7.33(d,J=7.1Hz, 1H), 6.97-6.89(m, 2H), 6.87(d, J=15.7Hz, 1H), 6.75(dd, J=1.4,8.0Hz, 1H), 6.60-6.55 (m, 4H), 4.95(bs, 2H), 4.33(d, J=6.0Hz, 2H). 3, 33391 536

CH CH H N-(2-Amino-phenyl)-3- {4-[2-(3,4,5- trimethoxy-phenyl)-vinyl]-phenyl]- acrylamide ¹H-NMR(CDCl₃), δ(ppm): 8.12(bs, 1H), 7.64 (d,J= 14.2Hz, 1H), 7.42(bs, 4H), 7.23(bs, 2H), 6.97(d, J= 14.2Hz, 1H),6.94-6.82(m, 4H), 6.70(s, 2H), 4.11(bs, 2H), 3.87(s, 6H), 3.84(s, 3H). 3392 537

CH CH H N-(2-Amino-phenyl)-3- {4-[2-(3,4,5- trimethoxy-phenyl)-vinyl]-phenyl}- acrylamide ¹H-NMR(DMSO-d₆), δ(ppm): 8.49(s, 1H), 7.58(d,J= 15.7Hz, 1H), 7.33(d, J=8.5Hz, 1H), 7.23(m, 4H), 7.00 (d, J=8.5Hz,1H), 6.73(d, J=5.0Hz, 2H), 6.69(d, J= 5.0Hz, 2H), 6.58(d, J=15.4Hz, 1H),6.53(bs, 2H), 6.47 (s, 2H), 3.85(s, 3H), 3.63(s, 6H). 3 393 538

CH CH H N-(2-Amino-phenyl)-3- {4-[(3-sulfamoyl- phenylamino)-methyl]-phenyl}-acrylamide ¹H-NMR(CD₃OD/CDCl₃), δ(ppm): 7.61(d, J=15.7 Hz, 1H),7.45(d, J=8.1Hz, 2H), 7.29(d, J=8.1Hz, 2H), 7.18(dd, J=8.0Hz, 2H),7.12(d, J=15.7Hz, 1H), 7.10 (m, 1H), 7.03(t, J=7.4Hz, 1H), 6.83-6.66(m,4H), 3.93 (bs, all NH signals). 1, 3, 33 394 539

CH CH H N-(2-Amino-phenyl)-3- (4-{[3-(3-morpholin-4-yl-propylsulfamoyl)- phenylamino]-methyl}- phenyl)-acrylamide¹H-NMR(CDCl₃), δ(ppm): 8.34(bs, 1H), 7.64(d, J= 15.4Hz, 1H), 7.37 (d,J=8.0Hz, 2H), 7.34(m, 1H), 7.26 (d, J=8.0Hz, 2H), 7.23(d, J=15.4Hz, 1H),7.14(d, J= 7.8Hz, 1H), 7.04(m, 2H), 6.74(m, 4H), 4.85(bs, 1H), 4.30(d,J=4.4Hz, 2H), 3.69(t, J=4.4Hz, 4H), 2.99(t, J= 5.8Hz, 2H), 2.40(bs, 6H),1.59(t, J=4.4Hz, 2H). 3, 33, 42 395 540

CH CH H N-(2-Amino-phenyl)-3- {4-[2-(3,4,5- trimethoxy-phenyl)-ethyl]-phenyl}- acrylamide ¹H-NMR(CDCl₃), δ(ppm): 8.53(s, 1H), 7.72(d,J=15.6 Hz, 1H), 7.38(d, J=7.7Hz, 2H), 7.33(m, 1H), 7.16(d, J= 7.7Hz,2H), 7.07(m, 1H), 6.79(m, 2H), 6.69(d, J= 15.6Hz, 1H), 6.41(s, 2H),4.04(bs, 2H), 3.91(s, 3H), 3.85(s, 6H), 2.94(m, 4H). 3, 32 396 541

CH CH H N-(2-Amino-phenyl)-3- {4-[(4-methoxy- phenylamino)-methyl]-phenyl}-acrylamide ¹H-NMR(DMSO-d₆), δ(ppm): 9.35(s, 1H), 7.56(d, J=7.5Hz, 2H), 7.52(d, J=15.4Hz, 1H), 7.40(d, J=7.5 Hz, 2H), 7.33(d,J=7.7Hz, 1H), 6.92(d, J=7.7Hz, 1H), 6.85(d, J=15.4Hz, 1H), 6.75(d,J=8.0Hz, 1H), 6.67 (d, J=8.6Hz, 2H), 6.58(m, 1H), 6.52(d, J=8.6Hz, 2H),5.84(t, J=5.5Hz, 1H), 4.23(d, J=5.5Hz, 2H), 3.61(s, 3H). 3, 33 397 542

CH CH H N-(2-Amino-phenyl)-3- {4-[(3,4-dimethoxy- phenylamino)-methyl]-phenyl}-acrylamide ¹H-NMR(CDCl₃), δ(ppm): 8.48(s, 1H), 7.60(d, J=15.4Hz, 1H), 7.27(m, 5H), 6.97 (t, J=7.5Hz, 1H), 6.70(m, 3H), 6.59(d,J=15.4Hz, 1H), 6.25(s, 1H), 6.12(d, J= 7.1Hz, 1H), 4.23(s, 2H), 3.93(bs,3H), 3.75(s, 3H), 3.73(s, 3H). 3, 33 398 543

CH CH H N-(2-Amino-phenyl)-3- (4-{[3-(1H-tetrazol-5-yl)-phenylamino]-methyl}- phenyl)-acrylamide ¹H-NMR(CD₃OD), δ(ppm): 7.75(d,J=15.2 Hz, 1H), 7.60(d, J=7.6Hz, 2H), 7.48(d, J=7.6Hz, 2H), 7.33(m, 3H),7.27(m, 3H), 7.20(m, 1H), 6.84(m, 2H), 5.48(bs, 5H), 4.46(s, 2H). 3, 33399 544

CH CH H N-(2-Amino-phenyl)-3- (4-{[4-(1H-tetrazol-5- ylmethyl)-phenylamino]-methyl}- phenyl)-acrylamide ¹H-NMR(CD₃OD), δ(ppm): 7.75(d,J=15.2Hz, 1H), 7.58(d, J=8.2Hz, 2H), 7.42 (d, J=8.2Hz, 2H), 7.29(m, 2H),7.20(m, 2H), 7.04(d, J=8.2Hz, 2H), 6.83(d, J= 15.2Hz, 1H), 6.67(d,J=8.2Hz, 2H), 5.48(bs, 5H), 4.39 (s, 2H). 4.16(s, 2H). 3, 33 400 545

CH CH H N-(2-Amina-phenyl)-3- {4-[(4-bromo- phenylamino)-methyl]-phenyl}-acrylamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.42(s, 1H), 7.62(d,J=8.5Hz, 2H), 7.59(d, J=15.6Hz, 1H), 7.45 (d, J=8.0Hz, 2H), 7.40(d,J=7.5Hz, 1H), 7.23(d, J= 8.5Hz, 2H), 6.98(d, J=7.5Hz, 1H), 6.92(d,J=15.6Hz, 1H), 6.80(d, J=8.0Hz, 1H), 6.66-6.57(m, 4H), 4.99(bs, 2H),4.34(d, J=5.8Hz, 2H). 3, 33 401 546

CH CH H N-(2-Amino-phenyl)-3- {4-[(3-bromo- phenylamino)-methyl]-phenyl}-acrylamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.36(s, 1H), 7.57(d,J=7.6Hz, 2H), 7.54(d, J=15.8 Hz, 1H), 7.40 (d, J=8.2Hz, 2H), 7.33(d,J=7.6Hz, 1H), 7.00-6.91(m, 2H), 6.86(d, J=15.8Hz, 1H), 6.74(d, J=8.2Hz,2H), 6.66-6.54(m, 4H), 4.93(bs, 2H), 4.30(d, J=5.3Hz, 2H). 3, 33 402 547

CH CH H N-(2-Amino-phenyl)-3- {4-[(4-iodo- phenylamino)-methyl]-phenyl}-acrylamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.36(s, 1H), 7.56(d,J=8.0Hz, 2H), 7.53(d, J=15.8Hz, 1H), 7.39 (d, J=8.0Hz, 2H), 7.35(m, 1H),7.31(d, J=8.2Hz, 2H), 6.92(d, J=7.1Hz, 1H), 6.85(d, J=15.8Hz, 1H), 6.75(d, J=7.7Hz, 1H), 6.57(t, J=8.0Hz, 1H), 6.52(t, J= 6.0Hz, 1H), 6.42(d,J=8.5Hz, 2H), 4.94(bs, 2H), 4.28 (d, J=6.0Hz, 2H). 3, 33 403 548

CH CH H N-(2-Amino-phenyl)-3- {4-[(3-iodo- phenylamino)-methyl]-phenyl]-acrylamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.40(s, 1H), 7.57(d,J=7.6 Hz, 2H), 7.53(d, J=15.6Hz, 1H), 7.40 (d, J=8.2Hz, 2H), 7.33(d,J=7.6Hz, 1H), 6.92(m, 3H), 6.84(m, 2H), 6.74(d, J=7.6Hz, 1H),6.60-6.50(m, 3H), 4.93(bs, 2H), 4.28(d, J=5.9Hz, 2H). 3, 33 404 549

CH CH H N-(2-Amino-phenyl)-3- (4-{[3-(2-hydroxy- ethoxy)-phenylamino]-methyl}-phenyl)- acrylamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.42(s, 1H),7.63(d, J=8.2Hz, 2H), 7.60(d, J=15.3Hz, 1H), 7.46 (d, J=8.2Hz, 2H),7.40(d, J=7.6Hz, 1H), 7.03-6.98(m, 2H), 6.91 (d, J=15.3Hz, 1H), 6.81(d,J=7.6Hz, 1H), 6.64(t, J=7.6 Hz, 1H), 6.36(t, J=5.9Hz, 1H), 6.28-6.22(m,3H), 4.99(bs, 3H), 4.61(s, 2H), 4.34(d, J=5.0Hz, 2H) 4.28(d, J=5.0Hz,2H). 3, 33 405 550

CH CH H N-(2-Amino-phenyl)-3- {4-[(4-ntro- phenylamino)-methyl]-phenyl}-acrylamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.38(s, 1H), 7.99 (d,J=9.1Hz, 2H), 7.85(t, J=5.9Hz, 1H), 7.60(d, J=7.6Hz, 2H), 7.54(d,J=15.8Hz, 1H), 7.40(d, J=7.6Hz, 2H), 7.34(d, J=7.6Hz, 1H), 6.94-6.92(m,1H), 6.88(d, J=15.8Hz, 1H), 6.75(d, J=7.6Hz, 1H), 6.68(d, J=9.1Hz, 2H),6.58(t, J=7.6 Hz, 1H), 4.94(bs, 2H), 4.46(d, J=5.9Hz, 2H) 3, 33 406 551

CH CH H N-(2-Amino-phenyl)-3- {4-[(3-nitro- phenylamino)-methyl]-phenyl}-acrylamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.37(s, 1H), 7.59(d,J=7.6Hz, 2H), 7.54(d, J=15.2Hz, 1H), 7.43(d, J=7.6 Hz, 2H), 7.36-7.28(m,4H), 7.05-6.98(m, 2H), 6.92(d, J=7.6Hz, 1H), 6.88(d, J=15.2Hz, 1H),6.75(d, J=7.6Hz, 1H), 6.58(t, J=7.6Hz, 1H), 4.96(bs, 2H), 4.39(d,J=5.3Hz, 2H). 3, 33 407 552

CH CH H N-(2-Amino-phenyl)-3- {4-[(4-chloro- phenylamino)-methyl]-phenyl}-acrylamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.43(s, 1H), 7.62(d,J=7.6Hz, 2H), 7.59(d, J=15.8Hz, 1H), 7.46(d, J=7.6 Hz, 2H), 7.40(d,J=7.6Hz, 1H), 7.12(d, J=8.8Hz, 2H), 6.98 (d, J=7.6Hz, 1H), 6.93(d,J=15.8Hz, 1H), 6.81(d, J=7.6Hz, 1H), 6.62(d, J=8.8Hz, 2H), 6.55(bs, 2H),4.99(bs, 2H), 4.46 (d, J=5.9Hz, 2H), 4.35(d, J=5.9Hz, 2H) 3, 33 408 553

CH CH H N-(2-Amino-phenyl)-3- {4-[(3-chloro- phenylamino)-methyl]-phenyl}-acrylamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.50(s, 1H), 7.65(d,J=8.2Hz, 2H), 7.61(d, J=15.4Hz, 1H), 7.47(d, J=7.6 Hz, 2H), 7.43(m, 1H),6.93(d, J=7.0Hz, 1H), 6.79(d, J=15.4 Hz, 1H), 6.68(m, 3H), 6.59(m, 3H),5.24(bs, 2H), 4.31(s, 2H). 3, 33 409 554

CH CH H N-(2-Amino-phenyl)-3- {4-[(4-fluoro- phenylamino)-methyl]-phenyl}-acrylamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.37(s, 1H), 7.63 (d,J=8.2Hz, 2H), 7.60(d, J=15.4Hz, 1H), 7.47(d, J=7.6Hz, 2H), 7.41(m, 1H),7.01-6.90(m, 4H), 6.75(d, J=7.6Hz, 1H), 6.67-6.59(m, 3H), 6.27(bs, 1H),4.95(bs, 2H), 4.27(s, 2H). 3, 33 410 555

CH CH H N-(2-Amino-phenyl)-3- {4-[(3-methylsulfanyl-phenylamino)-methyl]- phenyl}-acrylamide ¹H NMR(300 MHz, CD₃OD)δ(ppm):7.64(d, J=15.9 Hz, 1H), 7.47(d, J=7.5Hz, 2H), 7.32(d, J=7.5Hz, 2H),7.19(d, J=7.5Hz, 1H), 7.03(t, J=7.8Hz, 1H), 6.82(d, J=7.5Hz, 1H),6.77(d, J=7.8Hz, 1H), 6.70(d, J=15.9 Hz, 1H), 6.56(d, J=7.8Hz, 1H),6.49(s, 1H), 6.37(d, J= 7.8Hz, 1H), 4.29(s, 2H), 4.05(bs, 4H), 2.37(s,3H). 3, 33 411 556

CH CH H N-(2-Amino-phenyl)-3- {4-[(4-methylsulfanyl-phenylamino)-methyl]- phenyl}-acrylamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm):9.36(s, 1H), 7.57(d, J=7.5Hz, 2H), 7.53(d, J=15.8Hz, 1H), 7.40(d, J=7.9Hz, 2H), 7.34(d, J=7.9Hz, 1H), 7.07(d, J=8.3Hz, 2H), 6.92(d, J=7.5Hz,1H), 6.87(d, J=15.8Hz, 1H), 6.75(d, J=7.9Hz, 1H), 6.60-6.54(m, 3H),6.39(t, J=5.7Hz, 1H), 4.93(bs, 2H), 4.29(d, J=6.1Hz, 2H), 2.32(s, 3H),.3, 33 412 557

CH CH H N-(2-Amino-phenyl)-3- {4-[(5-bromo-pyridin-2- ylamino)-methyl]-phenyl}-acrylamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.36(s, 1H), 8.02(d,J=1.7Hz, 1H), 7.57-7.50(m, 4H), 7.38-7.32(m, 4H), 6.92(d, J=7.5Hz, 1H),6.86(d, J=16.3Hz, 1H), 6.75(d, J=7.9Hz, 1H), 6.59(d, J=7.5Hz, 1H),6.53(d, J=9.2Hz, 1H), 4.94(bs, 2H), 4.48(d, J=5.7Hz, 2H). 3, 33 413 558

CH CH H N-(2-Amino-phenyl)-3- [4-(naphthalen-1- ylaminomethyl)-phenyl]-acrylamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.37(s, 1H), 8.25(m,1H), 7.76(m, 1H), 7.57(m, 2H), 7.47(m, 4H), 7.33(d, J=7.0Hz, 1H),7.17(m, 1H), 7.07(d, J=8.2Hz, 1H), 6.99(t, J=5.3Hz, 1H), 6.92(d,J=7.0Hz, 1H), 6.85(d, J=16.4Hz, 1H), 6.74(d, J=7.6Hz, 1H), 6.57(t,J=7.6Hz, 1H), 6.36(t, J=7.6 Hz, 1H), 4.90(s, 2H), 4.54(d, J=5.3Hz, 2H).3, 33 414 559

CH CH H N-(2-Amino-phenyl)-3- {4-[(3-fluoro- phenylamino)-methyl]-phenyl}-acrylamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.39(s, 1H), 7.57(d,J=7.0Hz, 2H), 7.53(d, J=15.4Hz, 1H), 7.40(d, J=7.6 Hz, 2H), 7.36(d,J=7.6Hz, 1H), 7.02(q, J=7.6Hz, 1H), 6.90(m, 2H), 6.76(d, J=8.2Hz, 1H),6.58(m, 1H), 6.40(d, J=8.2Hz, 1H), 6.29(m, 2H), 4.90(s, 1H), 4.29(bs,2H), 4.02(s, 2H). 3, 33 415 560

N-(2-Amino-phenyl)-3-{3,5- dimethoxy-4-[(3,4,5- trimethoxy-phenylamino)-methyl]-phenyl}-acrylamide ¹H-NMR(CDCl₃), δ(ppm): 7.73(bs, 1H), 7.63(d,J=14.9Hz, 1H), 6.81(m, 3H), 6.70(m, 2H), 6.68-6.56 (m, 2H), 6.07(s, 2H),4.35(s, 2H), 3.86(s, 6H), 3.81(s, 6H), 3.75(s, 3H). 60 416 561

N-(2-Amino-3-hydroxy- phenyl)-3-{4-[(3,4,5- trimethoxy-phenylamino)-methyl]-phenyl}- acrylamide ¹H NMR(300 MHz, CDCl₃)δ(ppm): 9.22(s, 1H),9.11(s, 1H), 7.57(d, J=7.9Hz, 2H), 7.64(d, J=15.8Hz, 1H), 7.44(d,J=7.9Hz, 2H), 6.96(d, J=15.8Hz, 1H), 6.78(t, J=7.9 Hz, 1H), 6.23(t,J=7.9Hz, 1H), 6.16(d, J=7.9Hz, 1H), 6.09(t, J=6.2Hz, 1H), 5.89(s, 2H),4.77(bs, 2H), 4.27(d, J=5.7Hz, 2H), 5.89(s, 6H), 5.76(s, 3H). 3, 33 417562

CH CH H N-(2-Amino-phenyl)-3-(4- [(2,3,4-trimethoxy-phenylamino)-methyl]- phenyl}-acrylamide ¹H NMR(300 MHz, CDCl₃)δ(ppm):8.25(s, 1H), 7.74(d, J=15.5Hz, 1H), 7.44(d, J=7.9Hz, 2H), 7.37(d, J=7.9Hz, 2H), 7.34-7.29(m, 2H), 7.08 (t, J=7.5Hz, 1H), 6.82(t, J=7.5 Hz, 1H),6.79(m, 1H), 6.66(d, J=15.5Hz, 1H), 6.60(d, J=8.8 Hz, 1H), 6.31(d,J=8.8Hz, 1H), 4.36(s, 2H), 4.18(bs, 2H), 3.98 (s, 3H), 3.96(s, 3H),3.84(s, 3H). 3, 33 418 563

CH CH H N-(2-Amino-phenyl)-3-[4-({4- methoxy-3-[(3,4,5-trimethoxy-phenylamino)- methyl]-phenylamino}-methyl)-phenyl]-acrylamide ¹H NMR(300 MHz, CDCl₃)δ(ppm): 8.58(s, 1H),7.66(d, J=15.4Hz, 1H), 7.33-7.28(m, 3H), 7.23(d, J=7.0Hz, 2H), 7.04(t,J=7.0Hz, 1H), 6.77-6.70(m, 4H), 6.64(d, J=15.4 Hz, 1H), 6.53(d, J=7.5Hz,1H), 5.90(s, 2H), 4.27(s, 2H), 4.25 (s, 2H), 4.08(bs, 4H), 3.82(s, 6H),3.77(s, 6H). 3, 33 419 564

N-(2,3-Diamino-phenyl)-3- {4-[(3,4,5-trimethoxy- phenylamino)-methyl]-phenyl}-acrylamide ¹H NMR(300 MHz, CDCl₃)δ(ppm): 7.64(d, J=15.4Hz, 1H),7.48(d, J=7.5Hz, 2H), 7.35(d, J=7.5Hz, 2H), 7.31-7.24(m, 2H), 6.86(s,1H), 6.73(d, J=15.4Hz, 1H), 5.84(s, 2H), 4.27 (s, 2H), 4.00(bs, 6H),3.71(s, 6H), 3.68(s, 3H). 3, 33 420 565

CH CH H N-(2-Amino-phenyl)-3-{4-[(3- fluoro-4-methylsulfanyl-phenylamino)-methyl]- phenyl}-acrylamide ¹H-NMR(DMSO-d₆), δ(ppm):9.38(bs, 1H), 7.58(d, J=7.5Hz, 2H), 7.54(d, J=15.4Hz, 1H), 7.40(d, J=7.9Hz, 2H), 7.33(d, J=7.9Hz, 1H), 7.14(t, J=8.3Hz, 1H), 6.94-6.89(m, 2H),6.81(d, J=15.7Hz, 1H), 6.74(d, J=8.3Hz, 1H), 6.58(t, J=7.5Hz, 1H),6.43-6.38(m, 2H), 4.94(bs, 2H), 4.30(d, J=5.7Hz, 2H). 2.28(s, 3H). 3, 33421 566

CH CH H N-(2-Amino-phenyl)-3-{4-[(4- methylsulfanyl-3- trifluoromethyl-phenylamino)-methyl]- phenyl}-acrylamide ¹H-NMR(DMSO-d₆), δ(ppm):9.39(bs, 1H), 7.59(d, J=7.9Hz, 2H), 7.54(d, J=15.8Hz, 1H), 7.41(d,J=7.9Hz, 2H), 7.36(d, J=7.9Hz, 1H), 7.33(d, J=6.2Hz, 1H), 6.96-6.90(m,4H), 6.82 (d, J=15.8Hz, 1H), 6.79-6.74(m, 1H), 6.58(t, J=7.5Hz, 1H),4.95(bs, 2H), 4.35(d, J=6.2Hz, 2H). 2.35(s, 3H). 3, 33 422 567

N-(2-Amino-phenyl)-3-{3- nitro-4-[(3,4,5-trimethoxy-phenylamino)-methyl]- phenyl}-acrylamide ¹H-NMR(DMSO-d₆), δ(ppm):9.50(s, 1H), 8.09(s, 1H), 7.80(d, J=15.4Hz, 1H), 7.81(s, 2H), 7.34(d,J=7.9Hz, 1H), 6.94(d, J=7.5Hz, 1H), 6.88(d, J=15.4Hz, 1H), 6.76(d, J=7.9Hz, 1H), 6.58(t, J=7.5Hz, 1H), 6.26(t, J=6.2Hz, 1H), 5.90 (s, 2H),4.96(bs, 2H), 4.39(d, J=5.7Hz, 2H), 3.66(s, 6H), 3.51 (s, 3H). 3, 33 423568

N-(2-Amino-phenyl)-3-{3- amino-4-[(3,4,5- trimethoxy-phenylamino)-methyl]-phenyl}-acrylamide ¹H-NMR(DMSO-d₆), δ(ppm): 9.29(s, 1H), 7.72(d,J=15.4Hz, 1H), 7.33(m, 2H), 6.90(1H); 6.71(2H), 6.62(3H), 5.97(1H),5.87(2H), 5.49(2H), 4.96(2H), 4.10(2H), 3.65(6H), 3.51(3H). 3, 33 424569

N-(2-Amino-phenyl)-3-[6- (3,4-dimethoxy-phenyl)-pyridin-3-yl]-acrylamide LRMS: calc: 375.4, found: 376.4 3, 15, 33 425570

N-(4-Amino-thiophen-3-yl)- 3-{4-[(4-morpholin-4-yl-phenylamino)-methyl]- phenyl}-acrylamide ¹H-NMR(DMSO-d6), δ(ppm):9.64(bs, 1H), 7.65(d, J=7.9Hz, 2H), 7.60 (d, J=14.0Hz, 1H), 7.50(d,J=7.9Hz, 2H), 6.90(d, J=15.8Hz, 1H), 6.15(d, J=4.0Hz, 1H), 5.95(s, 2H),5.82(s, 1H), 4.89(bs, 2H), 4.33(d, J=5.7Hz, 2H), 3.71(s, 6H), 3.57(s,3H). 3, 33, 60

Example 85N-(2-Amino-phenyl)-4-(1H-benzimidazol-2-ylsulfanylmethyl)-benzamide(compound 126)

Step 1: 4-(1H-Benzimidazol-2-ylsulfanylmethyl)-benzoic acid methyl ester(compound 122)

Following the procedure described in Example 47, step 2, but using 119and substituting 121 for 63, the title compound 122 was obtained in 95%yield. LRMS=299.1 (M+1).

Step 2:N-(2-Amino-phenyl)-4(1H-benzimidazol-2-ylsulfanylmethyl)-benzamide (126)

Following the procedure described in Example 1, steps 4 and 5, butsubstituting 122 for 6, the title compound 126 was obtained in 62%yield. ¹H NMR: (DMSO-d₆) δ (ppm): 9.57 (s, 1H), 7.89 (d, J=8.2 Hz, 2H),7.55 (d, J=8.2 Hz, 2H), 7.53 (bs, 2H), 7.36 (bs, 2H), 7.14-7.08 (m, 3H),6.94 (t, J=8.2 Hz, 1H), 6.74 (d, J=6.9 Hz, 1H), 6.56 (t, J=8.0 Hz, 1H),4.87 (bs, 2H), 4.62 (s, 2H).

Example 87N-(2-Amino-phenyl)-4-[6-(2-morpholin-4-yl-ethylamino)-benzothiazol-2-ylsulfanylmethyl]-benzamide(compound 128)

Step 1: 4-(6-Amino-benzothiazol-2-ylsulfanylmethyl)-benzoic acid methylester (122)

Following the procedure described in Example 47, step 2, but using 120and substituting 121 for 63, the title compound 122 was obtained in 45%yield. LRMS=331.0 (M+1).

Step 2:4-[6-(2-Morpholin-4-yl-ethylamino)-benzothiazol-2-ylsulfanylmethyl]-benzoicacid methyl ester (compound 124)

To a solution of 4-(6-Amino-benzothiazol-2-ylsulfanylmethyl)-benzoicacid methyl ester 122 (800 mg, 2.42 mmol), in DMF (24 mL), were addedsuccessively solid 4-(2-chloroethyl)morpholine hydrochloride (296 mg,2.66 mmol), K₂CO₃ (611 mg, 5.08 mmol), Nal (363 mg, 2.42 mmol), Et₃N(370 μL, 2.66 mmol) and tetrabutylammonium iodide (894 mg, 2.42 mmol),The mixture was stirred at 120° C. for 24 h and more4-(2-chloroethyl)morpholine hydrochloride (296 mg, 2.66 mmol) was added.The mixture was stirred for 8 h at 120° C. and the solvent was removedin vacuo. The resulting black syrup was partitioned between H₂O andEtOAc. The organic layer was successively washed with HCl 1N andsaturated aqueous NaHCO₃. The precipitate was extracted twice withEtOAc, dried over MgSO₄ and concentrated. Purification by flashchromatography (MeOH/CHCl₃: 5:95 to 10:90) afforded 48 mg (4% yield) of124 as a light yellow oil. LRMS=444.1 (M+1).

Step 3:N-(2-Amino-phenyl)-4-[6-(2-morpholin-4-yl-ethylamino)-benzothiazol-2-ylsulfanylmethyl]-benzamide(compound 128)

Following the procedure described in Example 1, steps 4 and 5, butsubstituting 124 for 6, the title compound 128 was obtained in 76%yield. ¹H NMR: (Acetone-d₆) δ (ppm): 9.06 (bs, 1H), 7.98 (d, J=8.2 Hz,2H), 7.63 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.8 Hz, 2H), 7.29 (d, J=8.0 Hz,1H), 7.06 (d, J=2.2 Hz, 1H), 7.02-6.97 (m, 1H), 6.87-6.82 (m, 2H), 6.66(dt, J=7.4 Hz, 1.4 Hz, 1H), 4.63 (s, 2H), 3.64-3.60 (m, 4H), 3.25 (t,J=6.3 Hz, 2H), 2.63 (t, J=6.3 Hz, 2H), 2.54-2.42 (m, 4H).

Example 88 N-(2-Amino-phenyl)-4-(quinolin-2-ylsulfanylmethyl)-benzamide(compound 131)

Step 1: 2-(4-Bromo-benzylsulfanyl)-quinoline (compound 130)

Following the procedure described in Example 47, step 2, butsubstituting 129 for 63, the title compound 130 was obtained in 89%yield. LRMS=332.0 (M+1).

Step 2: N-(2-Amino-phenyl)-4-(quinolin-2-ylsulfanylmethyl)-benzamide(131)

Following the procedure described in Example 40, step 2, butsubstituting 129 for 42, the title compound 131 was obtained in 70%yield. ¹H NMR: (DMSO-d₆) δ (ppm): 9.62 (bs, 1H), 8.21 (d, J=8.8 Hz, 1H),8.00-7.89 (m, 4H), 7.79 (dd, J=6.8 Hz, 1.3 Hz, 1H), 7.68 (d, J=6.3 Hz,2H), 7.56 (t, J=6.8 Hz, 1H), 7.44 (d, J=8.7 Hz, 1H), 7.17 (d, J=8.2 Hz,1H), 6.99 (dt, J=7.9 Hz, 7.4 Hz, 1H), 6.79 (d, J=6.9 Hz, 1H), 6.61 (dt,J=7.7 Hz, 7.4 Hz, 1H), 4.69 (s, 2H).

Example 89 N-(2-Amino-phenyl)-4-(pyrimidin-2-ylaminomethyl)-benzamide(compound 134)

Step 1: 4-(Pyrimidin-2-ylaminomethyl)-benzoic acid methyl ester(compound 133)

Following the procedure described in Example 47, step 2, butsubstituting 132 for 63, the title compound 133 was obtained in 76%yield. LRMS=244.2 (M+1).

Step 2: N-(2-Amino-phenyl)-4-(pyrimidin-2-ylaminomethyl)-benzamide (134)

Following the procedure described in Example 1, steps 4 and 5, butsubstituting 129 for 6, the title compound 134 was obtained in 91%yield. ¹H NMR: (DMSO-d₆) δ (ppm): 9.6 (bs, 1H), 8.32 (d, J=4.9 Hz, 2H),7.97 (dt, J=9.9 Hz, 7.9 Hz, 2H), 7.85-7.83 (m, 1H), 7.47, (d, J=8.2 Hz,2H), 7.20 (d, J=7.9 Hz, 1H), 7.01 (dt, J=7.7 Hz, 7.4 Hz, 1H) 6.82 (d,J=7.9 Hz, 1H), 6.66-6.62 (m, 1H), 4.98 (bs, 2H), 4.61 (d, 2H).

Example 90N-2-Amino-phenyl)-4-(1-methyl-1H-imidazol-2-ylsulfanylmethyl]-benzamide(compound 139)

Step 1: [2-(4-lodo-benzoylamino)-phenyl]-carbamic acid tert-butyl ester(compound 135)

To a solution of di-tert-butyldicarbonate (39 g, 181 mmol) in THF (139mL) placed in a water bath, was added 1,2-phenylenediamine (15 g, 139mmol) and DMAP (1.7 g, 14 mmol). The mixture was stirred at r.t. for 16h and the solvent was removed in vacuo. The crude material waspartitioned between EtOAc and water. The organic layer was washed withHCl 1 N and then with aqueous saturated NaHCO₃. The combined organiclayers were washed with brine, dried over MgSO₄ and concentratedaffording the compound (18.9 g, 65% yield) as a light beige powder.LRMS=209.1 (M+1).

To a solution of 4-iodobenzoic acid (8.0 g, 32.3 mmol) in DMF (65 mL) atr.t., were successively added1-[3-(dimethylamino)propyl]-3-ethylcabodiimide hydrochloride (8.0 g,41.9 mmol) and 1-hydroxybenzotriazole (5.2 g, 38.7 mmol). The mixturewas stirred for 1 h and a solution of (2-amino-phenyl)-carbamic acidtert-butyl ester (6.3 g, 30.2 mmol) in DMF (20 mL) was added to themixture via cannula, followed by triethylamine (5.9 mL, 4.9 mmol). Themixture was stirred for 16 h and the solvent was removed in vacuo. Thecrude material was partitioned between chloroform and water. The organiclayer was washed with aqueous saturated NaHCO₃, dried over MgSO₄ andconcentrated to a light brown syrup which was crystallized in hot EtOAcor Et₂O, yielding 135 (9.3 g, 70% yield) as a white solid. LRMS=461.0(M+Na⁺).

Step 2: N-[2-tert-butoxycarbonylamino-phenyl)-terephtalamic acid methylester (compound 136)

Following the procedure described in Example 40, step 2, butsubstituting 135 for 42, the title compound 136 was obtained in 95%yield. LRMS=393.1 (M+Na⁺).

Step 3: [2(4-Hydroxymethyl-benzoylamino)-phenyl]-carbamic acidtert-butyl ester (137)

To a solution of 136 (7.5g, 20.6 mmol) in THF (40 mL), cooled down to−20° C. under N₂, was added a 1M solution of DIBAL-H (122 mL, 122 mmol)in toluene. After stirring for 18 h. at r.t., the mixture was cooleddown to 0° C. and carefully quenched by a dropwise addition of H₂O (10mL) and of 2N NaOH (5 mL). The aluminum salts were allowed to decant andthe supernatant was removed. The organic layer was washed with H₂O, 1 NHCl (6 times), satd. aqueous NaHCO₃, brine, dried over MgSO₄ andconcentrated (2.04 g, 43%). Purification of the crude material by flashchromatography (EtOAc/hexanes 50:50 to 70:30) afforded 137 (1.14 g, 16%yield) as a solid foam. LRMS=365.2 (M+Na⁺).

Step 4:{2-[4-(1-Methyl-imidazol-2-ylsulfanylmethyl)-benzoylamino]-phenyl}-carbamicacid tert-butyl ester (compound 138)

To a solution of N-methyl-2-mercaptoimidazole (28 mg, 0.25 mmol) in THF(1 mL), at r.t. under N₂atmosphere were successively added 137 (70 mg,0.20 mmol), triphenylphosphine (70 mg, 0.27 mmol) followed by dropwiseaddition of diethyl azodicarboxylate (48 μL, 0.31 mmol). The mixture wasstirred for 2 h and the solvent was removed in vacuo. Purification byflash chromatography using MeOH/CHCl₃ (5:95) as the eluent afforded thetitle compound 138 (81 mg), in 91% yield, which was found to containsome diethyl hydrazodicarboxylate residus. The compound was used as iswithout further purification.

Step 5:N-(2-Amino-phenyl-4-(1-methyl-1H-imidazol-2-ylsulfanylmethyl]-benzamide(compound 139)

Following the procedure described in Example 42, step 3, butsubstituting 138 for 46, the title compound 139 was obtained in 62%yield. ¹H NMR: (Acetone-d₆) δ (ppm): 9.07 (bs, 1H), 7.93 (d, J=8.2 Hz,2H), 7.37 (d, J=8.2 Hz, 2H), 7.29 (d, J=8.0 Hz, 1H), 7.10 (d, J=1.1 Hz,1H), 7.03-6.96 (m, 2H), 6.86 (dd, J=8.0 Hz, 1.4 Hz, 1H), 6.67 (dt, J=7.4Hz, 1.1 Hz, 1H), 4.63 (bs, 2H), 4.29 (s, 2H), 3.42 (s, 3H).

Example 91 N-(2-Amino-phenyl)-6-(3-methoxyphenyl)-nicotinamide (compound141)

To a mixture of 3-methoxyphenyl boronic acid (152 mg, 1.0 mmol) and 140(248 g, 1.0 mmol) were added benzene (8 mL) and ethanol (4 mL) followedby 2 M Na₂CO₃ aqueous solution (3.2 mL, 6.4 mmol). The reaction mixturewas stirred under nitrogen for 30 min and then Pd(PPh₃)₄ (58 mg, 0.05mmol) was quickly added. After 24 h of reflux, the mixture was cooled toroom temperature, filtered through a pad of celite and rinsed with ethylacetate (30 mL). The organic solution was washed with brine (5 mL),dried (MgSO₄), and concentrated. Purification by flash silica gelchromatography (Hexane/Ethyl acetate: 1/1) afforded 141 (302 mg, 95%yield). ¹H NMR (CDCl₃) δ (ppm): 9.11 (d, J=1.8 Hz, 1H), 8.30 (dd, J=8.4Hz, 1.8 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.52-7.47 (m, 1H), 7.36 (m,1H), 7.22 (m, 1H), 7.09-6.78 (m, 4H), 3.84 (s, 3H), 3.39 (br s, 2H).

Example 92N-(2-Amino-phenyl)-4-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-benzamide(compound 144)

Step 1: 4-(1-Oxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoic acid (compound143)

To a solution of benzene-1,2-carbaldehyde 142 (1.0 g, 7.46 mmol) in 10mL of acetic acid was added 4-aminomethylbenzoic acid (1.13 g, 7.46mmol). The reaction mixture was refluxed 5 min and cooled to the roomtemperature. A crystalline precipitate was formed and triturated withCH₂Cl₂ to produce the title compound 143 (1.29 g, 49%).

Step 2:N-(2-Amino-phenyl)-4-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-benzamide(compound 144)

To a solution of the carboxylic acid (0.32 g, 0.89 mmol) in DMF (8 mL)at rt, was added HOBt (0.16 g, 1.15 mmol) and EDC (0.25 g, 1.33 mmol)and the solution was stirred for 1.5 h. Lastly, phenylenediamine (0.12g, 1.07 mmol) was added and the mixture was allowed to stir for 18-20 h.DMF was removed in vacuo and the crude was partitioned between ethylacetate and H₂O. The organic layer was dried over Na₂SO₄ andconcentrated. Purification by column chromatography (CH₂Cl₂-MeOH (19:1))afforded 144 in 46% yield. ¹H NMR: (DMSO-d₆)

9.71 (s, 1H), 7.46 (d, J=8.0 Hz, 2H), 7.80 (d, J=8.0 Hz, 2H), 7.55-7.70(m, 3H), 7.46 (d, J=8.2 Hz, 2H), 7.20 (d, J=7.7 Hz, 1H), 7.02 (t, J=7.7Hz, 1H), 6.83 (d, J 8.0 Hz, 1H), 6.65 (t, J=7.4 Hz, 1H) 4.93 (bs, 2H),4.87 (s, 2H), 4.47 (s, 2H).

Example 94N-(2-Amino-phenyl)-4-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzamide(compound 149)

Phthalic anhydride 148 (1.3 g, 8.9 mmol) and 4-aminomethylbenzoic acidin 20 mL acetic acid were refluxing for 3 h, cooled to the roomtemperature and evaporated to yield a solid residue which was trituratedwith water, filtered off and dried to produce the intermediatecarboxylic acid (1.7 g, 68%). LMRS=282.0 (M+1).

Following a procedure analogous to that described in Example 92, step 2,but substituting the acid for 143, the title compound 149 was obtainedin 17% yield. ¹H NMR: (DMSO d₆)

9.59 (s, 1H), 7.82-7.91 (m, 6H), 7.40 (d, J=8.0 Hz, 2H), 7.11 (d, J=7.7Hz, 1H), 6.93 (t, J=7.7 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H), 6.55 (t, J=7.4Hz, 1H), 4.83 (bs, 4H).

Example 95N-(2-Amino-phenyl)-4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-benzamide(compound 152)

Step 1: 2-[2-(4-Hydroxy-phenyl)-ethyl]-isoindole-1,3-dione (compound150)

Following a procedure analogous to that described in Example 94, step 1,but substituting 4-aminomethylbenzoic acid for tyramine the titlecompound 150 was obtained in 48% yield. LMRS=268.0 (M+1).

Step 2: 4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2:yl)ethyl)-phenyltrifluoromethane-sulfonate (151)

To a solution of sodium hydride (90 mg, 25 mmol) in dry THF (20 mL) at0° C., 150 (500 mg, 8.9 mmol) was added followed by the addition of dryDMF (2 mL). The reaction mixture was stirred for 20 min at 0° C.,treated portionwise with PhN(Tf)₂, stirred for additional 2 h andevaporated to produce a solid material which was purified bychromatography on a silica gel column, (CH₂Cl₂-MeOH (19:1)) to provide151 (639 mg, 86% yield). LMRS=400.0 (M+1).

Step 3:N-(2-Amino-phenyl)-4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-benzamide(compound 152)

Following a procedure analogous to that described in Example 40, step 2,but substituting 151 for 42, the title compound 152 was obtained in 15%yield. ¹H NMR: (DMSO d₆)

9.57 (s, 1H), 7.78-7.87 (m, 6H), 7.31 (d, J 8.0 Hz, 2H), 7.12 (d, J=7.7Hz, 1H), 6.93 (t, J=6.9 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.56 (t, J=7.4Hz, 1H), 4.83 (bs, 2H), 3.85 (t, J=7.1 Hz, 2H), 3.00 (t, J=7.1 Hz, 2H).

Example 96N-(2-Amino-phenyl)-4-(4-oxo-4H-quinazolin-3-ylmethyl)-benzamide(compound 154)

A suspension of 4-aminomethyl benzoic acid (1.00 g, 6.60 mmol) in water(20 mL) was treated with Et₃N (0.86 mL, 6.60 mmol) followed by theaddition of isatoic anhydride 153 (980 mg, 6.00 mmol). The reactionmixture was heated 3 h at 40° C. and evaporated to form an oily residue,which was refluxing in formic acid (20 mL) for 7 h. Formic acid wasremoved in vacuum to produce a solid, which was triturated with waterand filtered off to provide the carboxylic acid (1.61 g, 96%).LMRS=281.0 (M+1).

Following a procedure analogous to that described in Example 92, step 2,but substituting the carboxylic acid for 143, the title compound 154 wasobtained was obtained in 43% yield. ¹H NMR: (DMSO d₆)

9.71 (s, 1H), 8.68 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 8.01 (d, J=8.0 Hz,1H), 7.92 (t, J=8.0, 2H), 7.78 (d, J=8.0 Hz, 1H), 7.63 (t, J=7.4, 1H),7.55 (d, J=7.7 Hz, 2H), 7.22 (d, J=7.4 Hz, 1H), 7.04 (t, J=7.1 Hz, 1H),6.85 (d, J=8.0 Hz, 1H), 6.67 (t, J=7.4 Hz, 1H), 5.35 (s, 2H).

Example 97N-(2-Amino-phenyl)-4-(4-oxo-4H-benzo[d][1,2,3]triazin-3-ylmethyl)-benzamide(compound 155)

A suspension of 4-aminomethyl benzoic acid (1.00 g, 6.60 mmol) in water(20 mL) was treated with Et₃N (0.86 mL, 6.60 mmol) followed by theaddition of isatoic anhydride (980 mg, 6.00 mmol). The reaction mixturewas heated 3 h at 40° C. and cooled to 0° C. The cold reaction mixturewas acidified with conc. HCl (5 mL) and treated drop wise with NaNO₂solution (520 mg, 7.5 mmol in 5 mL water) over 5 min period of time,then left overnight at room temperature. A precipitate formed which wascollected, washed with water and dried to provide the carboxylic acid(1.62 g, 96%). LMRS=282.0 (M+1).

Following a procedure analogous to that described in Example 92, step 2,but substituting the carboxylic acid for 143, the title compound 155 wasobtained in 27% yield. ¹H NMR: (DMSO d₆)

9.62 (s, 1H), 8.25 (t, J=6.7 Hz, 2H), 8.11 (ddd, J=7.1 Hz, 1H),7.93-7.98 (m, 3H), 7.49 (d, J=8.2 Hz, 2H), 7.13 (d, J=7.7 Hz, 1H), 6.94(t, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.57 (t, J=7.7 Hz, 1H), 5.66(s, 2H), 4.87 (bs, 2H).

Example 98N-(2-Amino-phenyl)-4-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzamide(compound 157)

Step 1: 4-[(2-Amino-benzoylamino)-methyl]-benzoic acid (compound 156)

To a suspension of 4-aminomethylbenzoic acid (5.09 g, 33.7 mmol) in H₂O(50 mL), was added Et₃N (4.7 mL, 33.7 mmol) followed by isatoicanhydride 153 (5.0 g, 30.6 mmol). The brown mixture was heated at 40° C.for 2 h until the mixture became homogeneous and then Et₃N was removedin vacuo. The resulting aqueous solution was acidified (10% HCl/H₂O) andthe mixture was partitioned between H₂O and ethyl acetate. The combinedorganic extracts were dried over Na₂SO₄, filtered and evaporated to give156 as a white solid (6.0 g, 72%). LMRS=271.0 (M+1).

Step 2:N-(2-Amino-phenyl)-4-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzamide(compound 157)

The carboxylic acid 156 (1.72 g, 6.36 mmol) was suspended in a solutionof NaOH (2.55 g, 63.6 mmol) in H₂O (12 mL). To this solution was addeddioxane (10 mL) until mixture became homogeneous. The solution wascooled to 0° C. in an ice-bath and methyl chloroformate (1.25 mL, 16.1mmol) was added portionwise over 2 h. After completion of the reaction,the excess methyl chloroformate and dioxane were removed in vacuo andthe mixture was diluted with methanol (80 mL) and H₂O (20 mL). Thesolution was heated to 50° C. for 1 h. until the cyclization wascomplete. Methanol was removed in vacuo and then the aqueous layer wasextracted with ethyl acetate. Subsequently, the aqueous phase wasacidified (10% HCl/H₂O) and extracted with ethyl acetate (2×300 mL).These organic extracts were combined, dried over Na₂SO₄, filtered andevaporated to dryness. The resulting crude was triturated with warmmethanol to afford the carboxylic acid as a white solid (1.7 g, 90%).LMRS=319.0 (M+Na).

Following a procedure analogous to that described in Example 92, step 2,but substituting the quinazolinedione carboxylic acid for 143, the titlecompound 157 was obtained. ¹H NMR: (DMSO-d₆)

11.56 (brs, 1H), 9.59 (brs, 1H), 7.96-7.88 (m, 3H), 7.67 (dt, J=8.4, 1.4Hz, 1H), 7.30 (d, J=7.8 Hz, 2H), 7.21 (t, J=7.5 Hz, 2H), 7.13 (d, J=6.9Hz, 1H), 6.92 (dt, J=6.9, 1.2 Hz, 1H), 6.75 (d, J=6.9 Hz, 1H), 6.57 (t,J=6.9 Hz, 1H), 5.15 (brs, 2H), 4.86 (brs, 2H).

Example 99N-(2-Amino-phenyl)-4-(1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzamide(compound 158)

Step 2:4-(1-Methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzoic acidmethyl ester

To a solution of the quinazolinedione carboxylic acid (1.0 g, 3.38 mmol)in DMF (7 mL), was added K₂CO₃ (1.4 g, 10.1 mmol) and the mixture wasthen cooled to 0° C. Subsequently, Mel (1.05 mL, 16.9 mmol) was addedand the mixture was allowed to warm to rt in the ice bath overnight.Excess methyl iodide and DMF were removed in vacuo and the crude waspartitioned between ethyl acetate and H₂O. The aqueous phase was washedagain with ethyl acetate, the combined organic extracts were dried overNa₂SO₄ and then concentrated in vacuo to yield the desired product as anoff-white solid (0.93 g, 85%). LMRS=325.0 (M+1).

Step 3:4-(1-Methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzoic acid

To a suspension of the methyl ester (1.25 g, 3.85 mmol) in methanol (35mL), was added 1N NaOH (30 mL, 38.5 mmol) and the mixture was heated to45-50° C. for 3 h. until it became homogeneous. Methanol was removed invacuo and the crude was partitioned between ethyl acetate and H₂O. Theaqueous phase was acidified (10% HCl/H₂O) and extracted with ethylacetate (2×300 mL). These organic extracts were dried over Na₂SO₄ andconcentrated in vacuo to afford product 5 as a white solid (1.15 g,96%). LMRS=311.0 (M+1).

Step 4:N-(2-Amino-phenyl)-4-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzamide(compound 158)

Following a procedure analogous to that described in Example 92, step 2,but substituting the carboxylic acid for 143, the title compound 158 wasobtained in 10% yield. ¹H NMR: (DMSO-d₆) δ 9.59 (brs, 1H), 8.03 (d,J=7.8 Hz, 1H), 7.89 (d, J=7.8 Hz, 2H) 7.80 (dt, J=6.8, 1.5 Hz, 1H), 7.49(d, J=8.7 Hz, 1H), 7.42 (d, J=8.1 Hz, 2H), 7.32 (t, J=7.7 Hz 1H), 7.13(d, J=7.8 Hz, 1H), 6.95 (t, J=7.6 Hz, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.57(t, J=7.5 Hz 1H), 5.21 (brs, 2H), 4.86 (brs, 2H), 3.54 (s, 3H).

Example 100N-(2-Amino-phenyl)-4-(2-methyl-4-oxo-4H-quinazolin-3-ylmethyl)-benzamide(compound 159)

A suspension of 156 (903 mg, 3.34 mmol) in acetic anhydride (15 mL) washeated at 50° C. for 1 h. Acetic anhydride was evaporated under vacuumand the solid material formed was dissolved in acetic acid (30 mL). Thissolution was refluxed 48 h and evaporated to form another solidmaterial, which was recrystallized from a mixture AcOEt/CHCl₃ to producethe intermediate carboxylic acid (420 mg, 43% yield). LMRS=385.0 (M+1).

Following a procedure analogous to that described in Example 92, step 2,but substituting the carboxylic acid for 143, the title compound 159 wasobtained in 49% yield. ¹H NMR: (DMSO) δ (ppm): 9.64 (bs, 1H), 8.17 (dd,J=8.0, 1.6 Hz, 1H), 7.95 (d, J=8.2 Hz, 2H), 7.95 (dd, J=8.8, 2.5 Hz,1H), 7.84 (ddd, J=7.6, 7.0, 1.5 Hz, 1H), 7.64 (d, J=7.7 Hz, 1H), 7.53(ddd, J=7.6, 7.6, 1.1 Hz, 1H), 7.33 (d, J=8.2 Hz, 2H), 7.14 (dd, J=7.7,1.1 Hz, 1H), 6.96 (ddd, J=7.6, 7.6, 1.5 Hz, 1H), 6.77 (dd, J=8.0, 1.4Hz, 1H), 6.58 (ddd, J=7.6, 7.6, 1.3 Hz, 1H), 5.46 (s, 2H), 4.89 (bs, 2H)2.5 (s, 3H, overlaps with the DMSO signals).

Example 101N-(2-aminophenyl)-2-(4-Methoxy-benzylamino)-thiazol-5-yl-amide (compound163)

Step 1: 4-Methoxybenzyl-thiourea (compound 161)

To a solution of thiocarbonyl diimidazole (1.23 g, 6.22 mmol, 1.5equiv.) in dry dichloromethane (10 mL), neat alkylamine 160 (4.15 mmol,1.0 equiv.) was added dropwise at 0° C., and the solution stirred from0° C. to 15° C. during 16 h. A solution of concentrated ammoniumhydroxide (3 mL, 45 mmol, 3.6 equiv.) in 1,4-dioxane (6 mL) was added at0° C. and stirred at room temperature for 7 h. The solution was dilutedwith ethyl acetate (250 mL), washed with brine (2×50 mL), dried (MgSO₄),filtered and concentrated. After purification by column chromatography(silica gel, elution 5% methanol in dichloromethane), 161 was obtainedas yellow solid (700.2 mg,3.6 mmol, 86% yield). ¹H NMR: (Acetone-d₆) δ(ppm): 7.53 (bs, 1H), 7.28 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H),6.67 (bs, 2H), 4.67 (s, 2H), 3.77 (s, 3H). LMRS=197.1 (M+1).

Step 2: 2-(4-Methoxybenzylamino)thiazole-5-carboxylic acid methyl ester(compound 162)

A solution of trans methyl-2-methoxyacrylate (461 mg, 3.97 mmol, 1equiv.) in 50% 1,4-dioxane in water (4 mL) stirred at −10° C., wastreated with N-bromosuccinimide (792 mg, 4.46 mmol, 1.12 equiv.),stirred at the same temperature for 1 h, transferred to a flaskcontaining the thiourea 161 (700.2 mg, 3.6 mmol) and the mixture wasstirred at 80° C. for 2 h. After cooling down to room temperature,concentrated NH₄OH (0.8 mL) was added, stirred for 10 min and theresulting precipitated filtered and washed with water, giving 363 mg(1.3 mmol, 36% yield) of 162, plus 454 mg additional (91% pure by HPLC)as residue from evaporation of the filtrated (ca. 77% overall yield). ¹HNMR: (Acetone-d₆) δ (ppm): 7.97 (bs, 1H), 7.72 (bs, 1H), 7.33 (d, J=8.1Hz, 2H), 6.90 (d, J=8.1 Hz, 2H), 4.52 (s, 2H), 3.78 (s, 3H), 3.75 (s,3H). LMRS=279.1 (M+1).

Step 3: N-(2-aminophenyl)-2-(4-Methoxy-benzylamino)-thiazol-5-yl-amide(compound 163)

Following the procedure described in Example 1, steps 4 and 5, butsubstituting 162 for 6, the title compound 163 was obtained in 50%yield. ¹H-NMR (methanol-d4), δ (ppm): 7.86 (s, 1H), 7.29 (d, J=8.8 Hz,2H), 7.11 (dd, J=8.0 Hz, 1.4 Hz, 1H), 7.04 (dt, J=8.0 Hz, 1.4 Hz, 1H),6.90 (d, J=8.8 Hz, 2H), 6.86 (m, 1H), 6.74 (dt, J=7.4 Hz, 1.4 Hz, 1H),4.85 (bs, 4H), 4.45 (s, 2H), 3.78 (s, 3H).

Examples 102-121

Examples 102 to 121 describe the preparation of compounds 164 to 183using the same procedures as described for compounds 62 to 163 inExamples 47 to 101. Characterization data are presented in Tables 4a and4b.

TABLE 4a Characterization of Compounds Prepared in Examples 102-121

Ex. Cpd W Y Z Name Characterization Schm 102 164

CH CH N-(2-Amino-phenyl)-4- [(3,4,5-trimethoxy- phenylamino)-methyl]-benzamide ¹H NMR: (Acetone-d₆)δ(ppm): 9.09(bs, 1H), 7.99 (d, J=8.2Hz,2H), 7.54(d, J=8.0Hz, 2H), 7.29(d, J=7.7Hz, 1H), 7.00(t, J=6.6Hz, 1H),6.86(dd, J=8.0Hz, 1.1Hz, 1H), 6.67(t, J=8.0Hz, 1H), 5.99 (s, 2H),5.46(bs, 1H), 4.64(bs, 2H), 4.43(s, 2H), 3.69(s, 6H), 3.60(s, 3H). 11103 165

N CH N-(2-Amino-phenyl)-6-(3- hydoxymethyl-phenyl)- nicotinamide ¹HNMR(20% CD₃OD in CDCl₃)δ(ppm): 9.14(d, J=1.8Hz, 1H), 8.33(dd, J=8.4Hz,1.8Hz, 1H), 7.93 (s, 1H), 7.82(m, 2H), 7.50-7.40(m, 2H), 7.22-6.45 (m,4H), 4.69(s, 2H). 15 104 166

CH CH N-(2-Amino-phenyl)-4-(3- methoxy-phenyl)- benzamide ¹HNMR(CD₃OD)δ(ppm): 7.98(d, J=8.4Hz, 2H), 7.65(d, J=8.4Hz, 2H),7.31-7.04(m, 5H), 6.92-6.80(m, 3H), 3.84(s, 3H). 15 105 167

CH N N-(2-amino-phenyl)-6-(4- methoxy-benzylamino)- nicotinamide ¹HNMR(DMSO-d₆)δ(ppm): 9.33(s, 1H), 8.61 (d, J=2.5Hz, 1H), 7.89(dd,J=8.8Hz, 2.2Hz, 1H), 7.57(t, J=5.8Hz, 1H), 7.24(d, J=8.52Hz, 2H),7.11(d, J=7.69Hz, 1H), 6.90(m, 3H), 6.73(d, J=8.0Hz, 1H), 6.50-6.58(m,2H), 4.83(s, 2H), 4.45(d, J=5.8Hz, 2H), 3.70(s, 3H). 6 106 168

CH N N-(2-amino-phenyl)-6-[2-(4- methoxy-phenyl)-ethylamino]-nicotinamide ¹H NMR(DMSO-d₆)δ(ppm): 9.42(s, 1H), 8.72 (d,J=2.5Hz, 1H), 7.97(dd, J=8.8Hz, 2.5Hz, 1H), 7.23(m, 4H), 6.81-7.03(m,4H), 6.64(m, 1H), 6.56(d, J=9.1Hz, 1H), 4.92(s, 2H), 3.78(s, 3H),3.55(m, 2H), 2.85(t, J=7.3Hz, 2H). 6 107 169

CH CH N-(2-Amino-phenyl)-4-[(4,6- dimethoxy-pyrimidin-2-ylamino)-methyl]- benzamide ¹H NMR: (DMSO-d₆)δ(ppm): 9.63(bs, 1H), 7.95(d, J=7.9Hz, 2H), 7.85-7.82(m, 1H), 7.48(d, J=7.9Hz, 2H), 7.20(d,J=7.1Hz, 1H), 7.03(dt, J=7.6Hz, 7.4Hz, 1H), 6.81(d, J=7.9Hz, 1H), 6.63(dt, J=7.9Hz, 7.7Hz, 1H), 4.94(bs, 2H), 4.54(d, J=6.0Hz, 2H), 3.79(bs,6H). 11 108 170

CH CH N-(2-Amino-phenyl)-4- (quinolin-2- ylsulfanylmethyl)-benzamide ¹HNMR: (DMSO-d₆)δ(ppm): 9.62(bs, 1H), 8.21 (d, J=8.8Hz, 1H), 8.00-7.89(m,4H), 7.79(dd, J=6.8Hz, 1.3Hz, 1H), 7.68(d, J=6.3Hz, 2H), 7.56(t,J=6.8Hz, 1H), 7.44(d, J=8.7Hz, 1H), 7.17 (d, J=8.2Hz, 1H), 6.99(dt,J=7.9Hz, 7.4Hz, 1H), 6.79(d, J=6.9Hz, 1H), 6.61(dt, J=7.7Hz, 7.4Hz, 1H),4.69(s, 2H). 11 109 171

N CH N-(2-Amino-phenyl)-6-(4- methoxy-benzylsulfanyl)- nicotinamide ¹HNMR: (DMSO-d₆)δ(ppm): 9.06(bs, 1H), 8.17 (dt, J=10.9Hz, 9.0Hz, 1H),7.46(d, J=8.5Hz, 1H), 7.39(d, J=8.2Hz, 2H), 7.21-7.13(m, 2H), 7.01 (dt,J=7.6Hz, 7.4Hz, 1H), 6.91(d, J=8.5Hz, 2H), 6.80(d, J=7.9Hz, 1H), 6.62(t,J=7.4Hz, 1H), 5.01 (bs, 2H), 4.47(s, 2H), 3.76(s, 3H). 12 110 172

CH CH N-(2-Amino-phenyl)-4- (benzothiazol-2- ylsulfanylmethyl]-benzamide ¹H NMR: (DMSO-d₆)δ(ppm): 8.01(d, J=8.0Hz, 1H), 7.93(d,J=8.2Hz, 2H), 7.90(dd, J=4.4Hz, 0.6 Hz, 1H), 7.63(d, J=8.2Hz, 2H),7.48(dt, J=8.0Hz, 0.8Hz, 1H), 7.37(td, J=7.1Hz, 1.1Hz, 1H), 7.14 (d,J=7.1Hz, 1H), 6.96(t, J=6.3Hz, 1H), 6.76(d, J=7.7Hz, 1H), 6.58(t,J=6.6Hz, 1H), 4.88(s, 2H), 4.73(s, 2H). 11 112 174

CH N N-(2-amino-phenyl)-6-[2-(4- fluoro-phenyl)-ethylamino]-nicotinamide ¹H NMR(DMSO-d₆)δ(ppm): 9.34(s, 1H), 8.64 (d, J=2.5Hz, 1H),7.89(dd, J=9Hz, 2Hz, 1H), 7.16-7.22(m, 3H), 7.06-7.20(m, 3H), 6.90-6.96(m, 1H), 6.72-6.78(m, 1H), 6.46-6.60(m, 2H), 4.92(s, 2H), 3.50(m, 2H),2.92(m, 2H). 6 113 175

CH N N-(2-amino-phenyl)-6-(4- fluoro-benzylamino)- nicotinamide ¹HNMR(DMSO-d₆)δ(ppm): 9.34(s, 1H), 8.61 (d, J=2.2Hz, 1H), 7.91(dd,J=8.8Hz, 2.2Hz, 1H), 7.66(t, J=6Hz, 1H), 7.32-7.37(m, 2H), 7.08-7.38 (m,3H), 6.93(m, 1H), 6.74(m, 1H), 6.52-6.58(m, 2H), 4.84(s, 2H), 4.51(d,J=6.0Hz) 6 114 176

CH N N-(2-amino-phenyl)-6- (3,4,5-trimethoxy- benzylamino)-nicotinamide¹H NMR(DMSO-d₆)δ(ppm): 9.34(s, 1H), 8.63 (d, J=2.2Hz, 1H), 7.92(dd,J=8.8Hz, 2.2Hz, 1H), 7.57(t, J=6Hz, 1H), 7.10(m, 1H), 6.93(m, 1H),6.74(m, 1H), 6.66(s, 2H), 6.56(m, 2H), 4.84(s, 2H), 4.45(d, J=6Hz, 2H),3.73(s, 6H), 3.31(s, 3H). 6 115 177

CH CH N-(2-Amino-phenyl)-4-(5- phenyl-[1,3,4]oxadiazol-2-ylsulfanylmethyl]- benzamide ¹H NMR: (Acetone-d₆)δ(ppm): 9.08(bs, 1H),8.02(dd, J=7.1Hz, 1.9Hz, 4H), 7.69(d, J=8.5Hz, 2H), 7.62-7.57(m, 3H),7.28(d, J=7.7Hz, 1H), 7.03-6.97(m, 1H), 6.86(d, J=6.6Hz, 1H), 6.67(t,J=7.7Hz, 1H), 4.70(s, 2H), 4.63(bs, 2H). 14 116 178

N CH N-(2-aminophenyl)-6-(2- phenylamino-ethylamino)- nicotinamide¹H-NMR(CD₃OD-d4),δ(ppm): 8.67(d, J=2.2Hz, 1H), 7.97(dd, J=8.9Hz, 2.5Hz,1H), 7.58(m, 1H), 7.51(m, 1H), 7.15(dd, J=7.7Hz, 1.1Hz, 1H), 7.08 (m,2H), 6.89(dd, J=8.0Hz, 1.4Hz, 1H), 6.76(dt, J=7.7Hz, 4.4Hz, 1H), 6.67(t,J=7.7Hz, 2H), 6.60 (m, 2H), 4.87(bs, 4H), 3.60(t, J=6.3Hz, 2H), 3.35 (t,J=6.3Hz, 2H). 11 117 179

CH CH N-(2-Amino-phenyl)-4-(2,4- dioxo-4H- benzo[e][1,3]oxazin-3-ylmethyl)-benzamide ¹H NMR: (DMSO-d₆)δ(ppm): 9.62(s, 1H), 8.00 (dd,J=8.2Hz, 1.9Hz, 1H), 7.80-7.92(m, 3H), 7.42-7.50 (m, 4H), 7.13(d,J=7.1Hz, 1H), 6.95 (ddd, J=8.0Hz, 1.6Hz, 1H), 6.75(dd, J=8.0Hz, 1.4Hz,1H), 6.57(t, J=7.7Hz, 1H), 5.13(s, 2H), 4.87(bs, 2H). 11 118 180

CH CH N-(2-Amino-phenyl)-4-(4- ethyl-4-methyl-2,6-dioxo-piperidin-1-ylmethyl)- benzamide ¹H NMR: (DMSO-d₆)δ(ppm): 9.59(s, 1H),7.88 (d, J=8.2Hz, 2H), 7.31(d, J=8.2Hz, 2H), 7.13(d, J=7.4Hz, 1H),6.95(t, J=8.0Hz, 1H), 6.75(d, J=8.0Hz, 1H), 6.57(t, J=7.4Hz, 1H),4.87(s, 2H), 4.86(bs, 2H), 2.61(s, 2H), 2.55(s, 2H), 1.31(q, J=7.7Hz,2H), 0.91(s, 3H), 0.80(t, J=7.4Hz, 3H). 11 119 181

CH CH N-(2-Amino-phenyl)-4-(1- ethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3- ylmethyl)-benzamide ¹H NMR: (CDCl₃)δ(ppm):8.23(dd, J=7.8Hz, 1.5 Hz, 1H), 8.01(bs, 1H), 7.80(d, J=8.0Hz, 2H),7.71-7.65(m, 1H), 7.55(d, J=8.2Hz, 2H), 7.27-7.20(m, 3H), 7.05(dt,J=7.7, 1.5Hz, 1H), 6.81-6.77(m, 2H), 5.29(bs, 2H), 4.18(q, J=7.3 Hz,2H), 3.86(bs, 2H), 1.33(t, J=7.1Hz, 3H). 19 120 182

CH CH N-(2-Amino-phenyl)-4-(4,6- dimethyl-pyrimidin-2-ylsulfanylmethyl)- benzamide ¹H NMR: (DMSO-d₆)δ(ppm): 9.66(bs, 1H), 7.96(d, J=7.9Hz, 2H), 7.61(d, J=7.9Hz, 2H), 7.21(d, J=7.9Hz, 1H),7.04-6.99(m, 2H), 6.82(d, J=7.9 Hz, 1H), 6.64(t, J=7.4Hz, 1H), 4.49(s,2H), 2.42(s, 6H). 11 121 183

CH CH N(2-Amino-phenyl)-4-(4- trifluoromethyl-pyrimidin-2-ylsulfanylmethyl)benzamide ¹H NMR: (DMSO-d₆)δ(ppm): 9.66(bs, 1H), 9.07(d, J=5.2Hz, 1H), 7.97(d, J=7.4Hz, 2H), 7.78 (d, J=4.7Hz, 1H), 7.63(d,J=7.4Hz, 2H), 7.19(d, J=7.7Hz, 1H), 7.01(dt, J=7.7Hz, 7.4Hz, 1H),6.81(d, J=8.2Hz, 1H), 6.64(dt, J=7.4Hz, 7.1Hz, 1H), 4.94(bs, 2H),4.57(s, 2H). 11

TABLE 4b

Ex. Cpd W Y Z Name Characterization Schm 123 187

CH CH N-(2-Aminophenyl)- 4-[3-(pyridin-2ylmethyl-aminomethyl)phenyl)]-benzamide ¹H NMR(20% CD₃OD in CDCl₃)δ(ppm): 8.46(m,1H), 7.95(d, J=8.4Hz, 2H), 7.64-6.70(m, 14 H), 3.80(br s, 4H). 21 124188

CH CH Biphenyl-4,4′-dicarboxylic acid bis-[(2-amino-phenyl)-amide] ¹HNMR(CD₃OD)δ(ppm): 9.80(bs, 2H), 8.16 (d, J=7.9Hz, 4H), 7.96(d, J=7.9Hz,4H), 7.23(d, J=7.4 Hz, 2H), 7.03(dd, J=6.9, 7.4Hz, 2H), 6.84(d, J=8.2Hz, 2H), 6.66(dd, J=6.9, 7.7Hz, 2H), 5.06(bs, 4H).  1 125 189

CH CH N-(2-Amino-phenyl)-4-[4-{(3,4,5- trimethoxy-phenylamino)-methyl}-phenyl]-benzamide ¹H NMR(DMSO-d₆)δ(ppm): 10.15(1H, brs), 8.17(2H, d, J=8.0), 7.90(2H, d, J=8.2), 7.87(1H, brs), 7.72(1H, d, J=6.6),7.54(2H, m), 7.40(1H, d, J=8.5), 7.25(1H, m), 7.16(1H, d, J=7.4),7.07(1H, m), 6.08 (2H, s), 4.42(2H, s), 3.73(6H, s), 3.58(3H, d, J=0.8)21 126 190

CH CH N-(2-Amino-phenyl)- 4-[4-{(4-methoxy-phenylamino)-methyl}-phenyl]-benzamide 1H NMR(DMSO-d₆)δ(ppm): 10.03(lH, brs), 8.17(2H, d, J=7.7), 7.88(3H, m), 7.76(1H, d, J=7.1), 7.52 (2H, m), 7.35(1H,d, J=8.0), 7.17(1H, m), 7.08-6.93 (6H, m), 4.50(3H, s), 3.75(2H, s) 21128 193

CH CH N-(2-Amino-phenyl)- 4-(3-methyl-but-3- en-1-ynyl)-benzamide LRMScalc: 276.03, found: 277.2(MH)⁺ 22 129 194

CH CH N-(2-Amino-phenyl)-4-(1-hydroxy- cyclohexylethynyl)-benzamide LRMScalc: 334.4, found: 335(MH)⁺ 22 130 195

CH CH N-(2-Amino-phenyl)- 4-(3-hydroxy-3- methyl-but-1-ynyl)-benzamideLRMS calc: 294.35, found: 295.1(MH)⁺ 22 131 196

CH CH N-(2-Amino-phenyl)- 4-phenylethynyl-benzamide LRMS calc: 312.37,found: 313.2(MH)⁺ 22 180 320

CH CH N-(2-Amino-phenyl)- 4-[(5-chloro-benzooxazol-2-ylamino)-methyl]-benzamide ¹H NMR: (Acetone-d₆)δ(ppm): 9.67(s, 1H),8.85(s, 1H), 8.01(d, J=8.2Hz, 2H), 7.55(d, J=8.2Hz, 2H), 7.45(d,J=8.8Hz, 1H), 7.36(d, J=2.3Hz, 1H), 7.22(d, J=7.6Hz, 1H), 7.07(dd,J=8.8, 2.3Hz, 1H), 7.02(d, J=7.0Hz, 1H), 6.84(d, J=7.6Hz, 1H), 6.65(t,7.0Hz, 1H), 4.94(s, 2H), 4.67(d, J=5.3Hz 2H). 35 181 321

CH CH N-(2-Amino-phenyl)- 4{[4-(4-chloro-phenyl)-thiazol-2-ylamino]-methyl}-benzamide ¹H NMR: (DMSO-d₆)δ(ppm): 9.67(bs, 1H),8.36(t, J= 5.8Hz, 1H), 8.00(d, J=8.2Hz, 2H), 7.89 (d, J= 8.2Hz, 2H),7.57(d, J=8.2Hz, 2H), 7.48(d, J=8.2 Hz, 2H), 7.20(s, 1H), 7.02(t,J=8.5Hz, 1H), 6.83(d, J=7.7Hz, 1H), 6.65(t, J=7.1Hz, 1H), 4.92(bs, 2H),4.65(d, J=5.8Hz, 2H). 35 182 322

CH CH N-(2-Amino-phenyl)-4-[(5-bromo- benzothiazol-2-ylamino)-methyl]-benzamide ¹H NMR: (DMSO-d₆)δ(ppm): 6.97(s, 1H),8.78(bs, 1H), 8.01(d, J=8.8Hz, 2H), 8.00(s, 1H), 7.55(d, J= 8.2Hz, 2H),7.43-7.35(m, 2H), 7.22(d, J=7.6Hz, 1H), 7.03(t, J=7.0Hz, 1H), 6.83(d,J=7.6Hz, 1H), 6.65(t, J=7.6Hz, 1H), 4.94(s, 2H), 7.74(d, J=5.9 Hz, 2H).33, 34 183 323

CH CH N-(2-Amino-phenyl)-4-{5-[(3,4,5- trimethoxy-phenylamino)-methyl]-thiophen-2- ylmethyl}-benzamide LRMS calc: 489.58, found:490(MH)⁺ 21 184 325

CH CH N-(2-Amino-phenyl)-4-{6- [(pyridin-3-ylmethyl)-amino]-benzothiazol-2-ylsulfanylmethyl}- benzamide ¹H NMR: (Acetone-d₆)δ(ppm):8.65(d, J=1.4Hz, 1H), 8.44(dd, J=4.7, 3.0Hz, 1H), 7.97(d, J=8.2 Hz, 2H),7.81-7.77(m, 1H), 7.63(m, 3H), 7.33-7.26 (m, 2H), 7.09(d, J=2.5Hz, 1H),7.02-6.97(m, 1H), 6.91(dd, J=8.8, 2.5Hz, 1H), 6.86(dd, J=8.0, 1.4 Hz,1H), 6.69-6.64(m, 1H), 4.64(s, 2H), 4.47(s, 2H). 11 185 326

CH CH N-(2-Amino-phenyl)-4-{6- [(pyridin-2-ylmethyl)-amino]-benzothiazol-2-ylsulfanylmethyl}- benzamide ¹H NMR: (DMSO-d₆)δ(ppm):9.59(s, 1H), 8.52-8.51 (m, 1H), 7.89(d, J=8.24Hz, 2H), 7.71(td, J=7.7,1.9 Hz, 1H), 7.59-7.53(m, 3H), 7.34(d, J=8.0Hz, 1H), 7.25-7.21(m, 1H),7.12(d, J=6.9,Hz, 1H), 6.98-6.96 (m, 1H), 6.93(d, J=7.4Hz, 1H), 6.81(dd,J=9.1, 2.5Hz, 1H), 6.76-6.73(m, 1H), 6.67(t, J=5.8Hz, 1H), 6.56(t,J=7.4Hz, 1H), 4.87(s, 1H), 4.58(s, 2H), 4.38(d, J=6.3Hz, 2H). 11, 34 186327

CH CH N-(2-Amino-phenyl)-4-(1H- imidazo-2-ylsulfanylmethyl)- benzamide¹H NMR: (DMSO-d₆)δ(ppm): 12.23(bs, 1H), 9.59 (s, 1H), 7.86(d, J=8.2Hz,2H), 7.34(d, J=8.5Hz, 2H), 7.14-7.12(m, 2H), 6.94-6.92(m, 2H), 6.76(d,J=6.6 Hz, 1H), 6.57(t, J=7.4Hz, 1H), 4.87(s, 2H), 4.29(s, 2H). 14 187328

CH CH N-(2-Amino-phenyl)-4-morpholin- 4-ylmethyl-benzamide ¹H NMR:(CD₃OD)δ(ppm): 8.03(d, J=8.4Hz, 2H), 7.58(d, J=7.9Hz, 2H), 7.26(d,J=7.0Hz, 1H), 7.16 (t, J=6.6Hz, 1H), 6.98(d, J=7.0Hz, 1H), 6.85(t, J=7.5Hz, 1H), 3.78(t, J=4.4Hz, 4H), 3.68(s, 2H), 2.57-2.54(m, 4H). 37 188329

CH CH 3′,4′,5′-Trimethoxy- biphenyl-4-carboxylic acid(2-amino-phenyl)-amide ¹H NMR: (CD₃OD)δ(ppm): 8.14(d, J=7.9Hz, 2H), 7.85(d,J=8.4Hz, 2H), 7.29(d, J=7.9Hz, 2H), 7.17 (t, J=7.0Hz, 1H), 7.04(s, 2H),7.00(d, J=8.4Hz, 1H), 6.87(t, J=7.5Hz, 1H), 4.95(s, 6H), 4.01(s, 3H). 37189 330

CH CH 4-[(2-Amino-9-butyl- 9H-purin-6-ylamino)-methyl]-N-(2-amino-phenyl)-benzamide ¹H NMR: (DMSO-d₆)δ(ppm): 9.65(s, 1H),7.96(d, J= 7.7Hz, 2H), 7.95(bs, 2H) 7.78(s, 1H), 7.52(d, J= 7.9Hz, 2H),7.22(d, J=7.7Hz, 1H), 7.02(dd, J= 7.3, 8.0Hz, 1H), 6.8(d, J=8.0Hz, 1H),6.65(dd, J= 7.3, 7.7Hz, 1H), 5.91(s, 2H), 4.94(bs, 2H), 4.77(bs, 2H),4.01(t, J=7.1Hz, 1H), 1.78(m, 2H), 1.3(m, 2H), 0.95(t, J=7.4,Hz, 1H) 39190 331

CH CH N-(2-Amino-phenyl)-4-[(2-amino- 9H-purin-6-ylamino)-methyl]-benzamide ¹H NMR(DMSO-d₆)δ(ppm): 10.16(s, 1H), 9.60 (br, 1H),8.24(s, 1H), 8.08(d, J=8.0Hz, 2H), 7.62(m, 1H), 7.60(d, J=8.0Hz, 2H),7.40(m, 1H), 7.20(m, 2H), 7.08(m, 1H), 4.90(m, 2H), 4.6(br, 4H) 39 191332

CH CH N-(2-Amino-phenyl)-4-[(2-chloro- 9H-purin-6-ylamino)-methyl]-benzamide ¹H NMR(DMSO-d₆)δ(ppm): 9.67(m, 1H), 8.80(m, 1H), 8.24(s, 1H),7.99 (d, J=7.8Hz, 2H), 7.52(d, J= 7.8Hz, 2H), 7.21(d, J=7.8Hz, 1H),7,02(dd, J= 6.3, 7.8Hz, 1H), 6.82(d, J=8.1Hz, 1H), 6.70(d6, J= 6.3,8.1Hz, 1H), 4.94(br, 2H), 4.77(br, 2H) 39 192 333

CH CH N-(2-Amino-phenyl)-4-[(9-butyl- 2-chloro-9H-purin-6-ylamino)-methyl]-benzamide ¹H NMR(DMSO-d₆)δ(ppm): 9.60(s, 1H), 8.72(br, 1H),8.21(s, 1H), 7.92(d, J=8.0Hz, 2H), 7.45(d, J= 8.0Hz, 2H), 7.15(d,J=8.0Hz, 1H), 6.96(dd, J=6.7, 8.0Hz, 1H), 6.77(d, J=8.0Hz, 1H), 6.58(dd,J=6.7, 8.0Hz, 2H), 4.88(s, 1H), 4.71(m, 2H), 4.11(m, 2H), 1.76(m, 2H),1.25(m, 2H), 0.89(t, J=7.1Hz, 3H) 39 193 334

CH CH N-(2-Amino-phenyl)-4-[(1H- benzoimidazol-2-ylmethyl)-amino]-benzamide ¹H NMR: (DMSO-d₆)δ(ppm): 12.39(bs, 1H), 9.32(s, 1H),7.81(d, J=8.2Hz, 2H), 7.56(bs, 1H), 7.21-7.17 (m, 3H), 6.99-6.97(m, 2H),6.81(d, J=8.2Hz, 1H), 6.77(d, J=8.8Hz, 2H), 6.63(t, J=7.0Hz, 1H),4.85(s, 2H), 4.62(d, J=5.3Hz, 2H). 11 194 335

CH CH N-(2-Amino-phenyl)-4-(1-ethyl- 2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzamide ¹H NMR: (CDCl₃)δ(ppm): 8.23(dd, J=7.8,1.5Hz, 1H), 8.01(bs, 1H), 7.80(d, J=8.0Hz, 2H), 7.71-7.65 (m, 1H),7.55(d, J=8.2Hz, 2H), 7.27-7.20(m, 3H), 7.05(td, J=7.7, 1.5Hz, 1H),6.81-6.77(m, 2H), 5.29 (bs, 2H), 4.18(q, J=7.3Hz, 2H), 3.86(bs, 2H),1.33 (t, J=7.1Hz, 3H). MS: (calc.) 414.2;(obt.) 415.3(MH)⁺ 19 195 336

CH CH N-(2-Amino-phenyl)-4-(6-chloro- 2-methyl-4-oxo-4H-quinazolin-3-ylmethyl)-benzamide ¹H NMR: (DMSO)δ(ppm): 9.69(bs, 1H, NH), 8.71(s, 1H),8.16(d, J=2.5Hz, 1H), 8.01(d, J=8.2Hz, 2H), 7.95(dd, J=8.8, 2.5Hz, 1H),7.81 (d, J=8.8Hz, 1H), 7.74(d, J=8.2Hz, 2H), 7.20(d, J=7.1Hz, 1H),7.02(td, J=7.6, 1.5Hz, 1H), 6.82(dd, J=8.0, 1.4 Hz, 1H), 6.64(td, J=7.6,1.4Hz, 1H), 5.34(s, 2H), 4.94(bs, 2H). MS: (calc.) 404.1;(obt.)405.0(MH)⁺ 19 196 337

CH CH N-(2-Amino-phenyl)-4-(2-methyl- 4-oxo-4H-quinazolin-3-ylmethyl)-benzamide ¹H NMR: (DMSO)δ(ppm): 9.64(bs, 1H), 8.17(dd, J= 8.0,1.6Hz, 1H), 7.95(d, J=8.2Hz, 2H), 7.95(dd, J= 8.8, 2.5Hz, 1H), 7.84(ddd,J=7.6, 7.0, 1.5Hz, 1H), 7.64(d, J=7.7Hz, 1H), 7.53(ddd, J=7.6, 7.6,1.1Hz, 1H), 7.33(d, J=8.2Hz, 2H), 7.14(dd, J=7.7, 1.1Hz, 1H), 6.96(ddd,J=7.6, 7.6, 1.5Hz, 1H), 6.77(dd, J=8.0, 1.4Hz, 1H), 6.58(ddd, J=7.6,7.6, 1.3Hz, 1H), 5.46(s, 2H), 4.89(bs, 2H) 2.5(s, 3H). MS: (calc.)384.2;(obt.) 385.0(MH)⁺ 19 197 338

CH CH N-(2-Amino-phenyl)-4-(6,7- dimethoxy-4-oxo-4H-quinazolin-3-ylmethyl)-benzamide ¹H NMR: (DMSO)δ(ppm): 9.62(bs, 1H), 8.50(s, 1H),8.41(d, J=8.2Hz, 2H), 7.47(s, 1H), 7.46(d, J=7.7 Hz, 2H), 7.17(s, 1H),7.15(d, J=8.5Hz, 1H), 6.96 (ddd, J=7.7, 7.7, 1.1Hz, 1H), 6.76(d,J=6.9Hz, 1H), 6.58(dd, J=6.9, 6.9Hz, 1H), 5.26(s, 2H), 4.88 (bs, 2H),3.91(s, 3H), 3.87(s, 3H). MS: (calc.) 430.2; (obt.) 431.1(MH)⁺ 19 198339

CH CH N-(2-Amino-phenyl)-4-(6,7- difluoro-4-oxo-4H-quinazolin-3-ylmethyl)-benzamide ¹H NMR: (DMSO)δ(ppm): 9.66(bs, 1H), 8.69(s, 1H),8.07(dd, J=8.8, 10.4Hz, 1H), 7.96(d, J=8.2Hz, 2H), 7.82(dd, J=14.3,11.3Hz, 1H), 7.48 (d, J=8.2 Hz, 2H), 7.15(d, J=6.9Hz, 1H), 6.96(ddd,J=7.6, 7.6, 1.5Hz, 1H), 6.76(dd, J=8.1, 1.2Hz, 1), 6.58 (ddd, J=7.5,7.5, 1.2Hz, 1H), 5.28(s, 2H), 4.89(bs, 2H). MS: (calc.) 406.1;(obt.)407.0(MH)⁺ 19 199 340

CH CH N-(2-Amino-phenyl)-4-[1-(2- dimethylamino-ethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3- ylmethyl]-benzamide ¹H NMR: (DMSO)δ(ppm):9.61(bs, 1H), 8.09(dd, J= 7.8, 1.5Hz, 1H), 7.91(d, J=8.2Hz, 2H),7.81(ddd, J=7.8, 7.8, 1.6Hz, 1H), 7.52(d, J=8.2Hz, 1H), 7.42(d, J=8.2Hz,2H), 7.32(dd, J=7.6, 7.6Hz, 1H), 7.14(d, J=6.9Hz, 1H), 6.96(ddd, J=7.6,7.6, 1.5Hz, 1H), 6.77 (dd, J=7.8, 1.2Hz, 1H), 6.59(ddd, J=7.5, 7.5,1.2Hz, 1H), 5.22(s, 2H), 4.88(bs, 2H), 4.24(t, J=7.1Hz, 2H), 2.5(m, 2H)2.22(s, 6H). MS: (calc.) 457.2; (obt.) 458.1(MH)⁺ 19 200 341

CH CH N-(2-Amino-phenyl)-4-[1-(2- morpholin-4-yl-ethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3- ylmethyl]-benzamide ¹H NMR: (DMSO)δ(ppm):9.61(bs, 1H), 8.09(dd, J= 8.0, 1.6Hz, 1H), 7.92(d, J=8.2Hz, 2H),7.81(ddd, J=7.8, 7.8, 1.6Hz, 1H), 7.54(d, J=8.5Hz, 1H), 7.43(d, J=8.2Hz, 2H), 7.32(dd, J=7.4, 7.4Hz, 1H), 7.14(d, J=7.4Hz, 1H), 6.96(ddd,J=7.6, 7.6, 1.5Hz, 1H), 6.77(dd, J=8.0, 1.4Hz, 1H), 6.59(ddd, J=7.6,7.6, 1.4Hz, 1H), 5.22(s, 2H), 4.87(bs, 2H), 4.28(t, J=6.7Hz, 2H),3.50(t, J=4.5Hz, 4H), 2.58 (t, J=6.7Hz, 2H), 2.47-2.44(m, 4H). MS:(calc.) 499.2;(obt.) 500.3(MH)⁺. 19 201 342

CH CH N-(2-Amino-phenyl)-4-(6-bromo- 2-methyl-4-oxo-4H-quinazolin-3-ylmethyl)-benzamide ¹H NMR: (DMSO)δ(ppm): 9.65(bs, 1H), 8.25(d, J=2.5Hz, 1H), 7.99(ddd, J=8.5, 2.5, 0.8Hz, 1H), 7.95 (d, J=8.8Hz, 2H),7.60(d, J=8.8Hz, 1H), 7.34(d, J= 8.2 Hz, 2H), 7.14(d, J=7.4Hz, 1H),6.96(dd, J= 7.4, 7.4Hz, 1H), 6.76(d, J=8.0Hz, 1H), 6.59(dd, J= 7.4,7.4Hz, 1H), 5.45(s, 2H), 4.88(bs, 2H). MS: (calc.) 462.1;(obt.)463.1(MH)⁺. 19 202 343

CH CH N-(2-Amino-phenyl)-4-(2,4-dioxo- 1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3- ylmethyl)-benzamide ¹H NMR: (DMSO)δ(ppm): 9.61(bs, 1H),8.10(dd, J= 5.2, 0.5Hz, 1H), 7.91(d, J=8.2Hz, 2H), 7.40(d, J= 8.2Hz,2H), 7.15(d, J=7.1Hz, 1H), 6.98-6.94(m, 2H), 6.77(dd, J=8.0, 1.1Hz, 1H),6.58(dd, J=7.1, 7.1Hz, 1H), 5.12(s, 2H), 4.88(bs, 2H). MS: (calc.)392.1;(obt.) 393.0(MH)⁺. 43 203 344

CH CH N-(2-Amino-phenyl)-4-(6-bromo- 1-ethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzamide ¹H NMR: (DMSO)δ(ppm): 9.61(bs, 1H),8.15(d, J= 2.5Hz, 1H), 7.95(dd, J=9.1, 4.9Hz, 1H), 7.91(d, J= 8.2Hz,2H), 7.53(d, J=9.3Hz, 1H), 7.42(d, J= 8.2Hz, 2H), 7.15(d, J=6.9Hz, 1H),6.96(ddd, J= 7.6, 7.6, 1.5Hz, 1H), 6.77(dd, J=8.1, 1.5Hz, 1H), 6.59(ddd,J=7.6, 7.6, 1.4Hz, 1H), 5.20(s, 2H), 4.88 (bs, 2H) 4.14(q, J=7.0, 2H),1.21(t, J=7.0, 3H). MS: (calc.) 492.1;(obt.) 493.0(MH)⁺. 19 204 345

CH CH N-(2-Amino-phenyl)-4-[1-(4- methoxy-benzyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3- ylmethyl]-benzamide ¹H NMR: (DMSO)δ(ppm):9.62(bs, 1H), 8.10(dd, J= 7.7, 1.6Hz, 1H), 7.93(d, J=8.2Hz, 2H),7.71(ddd, J= 7.9, 7.9, 1.5Hz, 1H), 7.46(d, J=8.2Hz, 2H), 7.38 (d,J=8.2Hz, 2H), 7.31(d, J=7.4Hz, 1H), 7.26(d, J= 8.8Hz, 2H), 7.15(d,J=6.6Hz, 1H), 6.96(ddd, J= 7.6, 7.6, 1.2Hz, 1H), 6.89(d, J=8.8Hz, 2H),6.77 (dd, J=8.0, 1.4Hz, 1H), 6.59(ddd, J=7.5, 7.5, 1.2 Hz, 1H), 5.33(s,2H), 5.28(s, 2H), 4.89(bs, 2H), 3.71 (s, 3H). MS: (calc.) 506.2;(obt.)507.1(MH)⁺. 19 205 346

CH CH N-(2-Amino-phenyl)-4-(6-bromo- 4-oxo-4H-quinazolin-3-ylmethyl)-benzamide ¹H NMR: (DMSO)δ(ppm): 9.61(bs, 1H), 8.66(s, 1H), 8.24(d,J=2.5Hz, 1H), 8.00(dd, J=8.7, 2.3Hz, 1H), 7.95(d, J=8.2Hz, 2H), 7.68(d,J=8.8Hz, 1H), 7.48(d, J=8.2Hz, 2H), 7.15(d, J=8.0Hz, 1H), 7.96 (ddd,J=7.6, 7.6, 1.5Hz, 1H), 6.77(dd, J=8.0, 1.1 Hz, 1H), 6.59(dd, J=7.4,7.4Hz, 1H), 5.28(s, 2H), 4.87(bs, 2H). MS: (calc.) 448.0;(obt.)449.0(MH)⁺. 19 206 347

CH CH N-(2-Amino-phenyl)-4-(6-bromo- 4-oxo-4H-benzo[d][1,2,3]triazin-3-ylmethyl)-benzamide ¹H NMR: (DMSO)δ(ppm): 9.63(bs, 1H), 8.38(d, J=1.9Hz, 1H), 8.28(dd, J=8.8, 2.2Hz, 1H), 8.19(d, J= 8.8Hz, 1H), 7.95(d,J=8.0Hz, 2H), 7.50(d, J= 8.2Hz, 2H), 7.15(d, J=6.9Hz, 1H), 7.96(ddd, J=7.6, 7.6, 1.5Hz, 1H), 6.77(dd, J=8.0, 1.4Hz, 1H), 6.59(ddd, J=7.6, 7.6,1.4Hz, 1H), 5.67(s, 2H), 4.87 (bs, 2H). MS: (calc.) 449.0;(obt.)450.0(MH)⁺. 19 207 348

CH CH N-(2-Amino-phenyl)-4-(6-chloro- 4-oxo-4H-benzo[d][1,2,3]triazin-3-ylmethyl)-benzamide ¹H NMR: (DMSO)δ(ppm): 9.63(bs, 1H), 8.30-8.24 (m,2H), 8.15(ddd, J=8.6, 2.5, 0.8Hz, 1H), 7.95(d, J= 8.0Hz, 2H), 7.50(d,J=8.2Hz, 2HH), 7.15(d, J=8.0 Hz, 1H), 7.96(dd, J=7.4, 7.4Hz, 1H),6.77(d, J=8.0 Hz, 1H), 6.59(dd, J=7.4, 7.4Hz, 1H), 5.67(s, 2H), 4.88(bs,2H). MS: (calc.) 405.1;(obt.) 406.0(MH)⁺. 19 208 349

CH CH N-(2-Amino-phenyl)-4-[(3-fluoro- 2-pyridinyl-amino)-methyl]-benzamide ¹H NMR(acetone-d₆)δ(ppm): 9.07(bs, 1H), 8.02(d, J=8.2Hz, 2H),7.64-7.44(m, 3H), 7.33(dd, J=7.8, 1.5 Hz, 1H), 7.03(td, J=7.6, 1.5Hz,1H), 6.90(dd, J=8.0, 1.4Hz, 1H), 6.78(bs, 1H), 6.71(td, J=7.6, 1.4Hz,1H), 6.48(dd, J=8.1, 2.6Hz, 1H), 6.16(dd, J=7.7, 2.5Hz, 1H),4.76-4.55(m, 4H). HRMS(calc.): 336.1386, (found): 336.1389. 11 209 350

CH CH N-(2-Amino-phenyl)-4-[(3,4,5- trifluoro-2-pyridinyl-amino)-methyl]-benzamide ¹H NMR(acetone-d₆)δ(ppm): 9.06(bs, 1H), ABsystem(δ_(A)=8.02, δ_(B)=7.56, J=8.3Hz, 4H), 7.74-7.65 (m, 1H), 7.33(d,J=8.0, 1H), 7.03(td, J=7.6, 1.5Hz, 1H), 6.96-6.83(m, 2H), 6.71(td,J=7.6, 1.4Hz, 1H), 4.74(d, J=6.3Hz, 2H), 4.65(bs, 2H). 11 210 351

CH CH N-(2-Amino-phenyl)-4-(2,4-dioxo- 1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-ylmethyl)- benzamide ¹H NMR: (DMSO)δ(ppm): 9.61(bs, 1H),8.10(dd, J= 5.2, 0.5Hz, 1H), 7.91(d, J=8.2Hz, 2H), 7.40(d, J= 8.2Hz,2H), 7.15(d, J=7.1Hz, 1H), 6.98-6.94(m, 2H), 6.77(dd, J=8.0, 1.1Hz, 1H),6.58(dd, J=7.1, 7.1Hz, 1H), 5.12(s, 2H), 4.88(bs, 2H). MS: (calc.)392.1;(obt.) 393.0(MH)⁺. 43 211 352

CH CH N-(2-Amino-phenyl)-4-(5-phenyl- [1,2,4]oxadiazol-3-yl)-benzamide¹H NMR: (DMSO)δ(ppm): 9.85(bs, 1H), 8.24-8.19 (m, 6H), 7.79-7.66(m, 3H),7.20(d, J=7.5Hz, 1H), 7.00(dd, J=7.3, 7.3Hz, 1H), 6.80(d, J=7.9Hz, 1H),6.61(dd, J=7.3, 7.3Hz, 1H), 4.96(bs, 2H). MS: (calc.) 356.1;(obt.)357.0(MH)⁺. 50 212 353

CH CH N-(2-Amino-phenyl)-4-(5-methyl- [1,2,4]oxadiazol-3-yl)-benzamide¹H NMR: (DMSO)δ(ppm): 9.81(bs, 1H), 8.17-8.11 (m, 4H), 7.18(d, J=7.9Hz,1H), 6.99(dd, J=7.7, 7.7Hz, 1H), 6.79(d, J=7.9Hz, 1H), 6.61(dd, J= 7.5,7.5Hz, 1H), 4.94(bs, 2H), 2.70(s, 3H). MS: (calc.) 294.1;(obt.)295.0(MH)⁺. 50 213 354

CH CHN-(2-Amino-phenyl)-4-(5-piperidin-1-ylmethyl-[1,2,4]oxadiazol-3-yl)-benzamide1H NMR: (acetone)δ(ppm): 9.29(bs, 1H), 8.21(m, 4H), 7.31(d, J=8.0Hz,1H), 7.03(dd, J=7.0, 7.0Hz, 1H), 6.88(d, J=7.3Hz, 1H), 6.69(dd, J=7.3,7.3Hz, 1H), 4.68(bs, 2H), 3.94(s, 2H), 2.58(t, J=5.1Hz), 1.63-1.55(m,4H), 1.47-1.43(m, 2H). MS(Calc) 377.2;(Obt.) 378.3(MH)+ 50 214 355

CH CH N-(2-Amino-phenyl)-4-(5- morpholin-4-ylmethyl-[1,2,4]oxadiazol-3-yl)-benzamide 1H NMR: (acetone)δ(ppm): 9.28(bs, 1H),8.21(m, 4H), 7.31(d, J=8.1Hz, 1H), 7.03(dd, J=7.0, 7.0 Hz, 1H), 6.88(d,J=7.3Hz, 1H), 6.69(dd, J=7.3, 7.3Hz, 1H), 4.67(bs, 2H), 4.01(s, 2H),3.66(t, J=4.8Hz), 2.65 (t, J=4.4Hz). MS: (Calc.) 379.2;(Obt.):380.2(MH)+ 50 215 356

CH CH N-(2-Amino-phenyl)-4-(5-propyl- [1,2,4]oxadiazol-3-ylmethyl)-benzamide ¹H NMR: (DMSO)δ(ppm): 9.62(s, 1H), 7.93(d, J= 7.9Hz, 2H),7.42(d, J=7.9Hz, 1H), 7.16(d, J=7.5 Hz, 1H), 6.97(t, J=7.0Hz, 1H), 6.77(d, J=7.9Hz, 1H), 6.59(t, J=7.5Hz, 1H), 4.88(s, 2H), 4.16(s, 2H),2.87(t, 7.0, 2H), 1.72(q, J=7.5Hz, 2H), 0.92(t, J= 7.0Hz, 3H).(MH)⁺:337.2. 50 216 357

CH CH N-(2-Amino-phenyl)-4-(5-pyridin- 3-yl-[1,2,4]oxadiazol-3-ylmethyl)-benzamide ¹H NMR: (DMSO)δ(ppm): 9.64(s, 1H), 9.24 d, J= 1.8Hz,1H); 8.86(dd, J=1.3Hz, J=4.8Hz, 1H), 8.45(dd, J=1.8Hz, J=6.2Hz, 1H),7.96(d, J=7.9 Hz, 2H), 7.66(dd, J=4.8Hz, J=7.9Hz, 1H), 7.50(d, J=8.4Hz,2H), 7.16(d, J=7.5Hz, 1H), 6.96(t, J= 7.0Hz, 1H), 6.77(d, J=7.5Hz, 1H),6.59(t, J=7.5 Hz, 1H), 4.89(s, 2H), 4.31(s, 2H).(MH)⁺. 372.3. 50 217 358

CH CH N-(2-Amino-phenyl)-4-(5-pyridin- 4-yl-[1,2,4]oxadiazol-3-ylmethyl)-benzamide ¹H NMR: (DMSO)δ(ppm): 9.63(s, 1H), 8.87(d, J= 6.2Hz,2H); 7.95-8.02(m, 3H), 7.50(d, J=7.9 Hz, 2H), 7.16(d, J=7.5Hz, 2H),6.97(t, J=7.0Hz, 1H), 6.77(d, J=7.0Hz, 1H), 6.59(t, J=7.9Hz, 1H), 4.89(s, 2H), 4.33(s, 2H).(MH)⁺: 372.3. 50 218 359

CH CH 4-(5-Acetylamino-4-cyano- thiophen-2-ylmethyl)-N-(2-amino-phenyl)-benzamide 1H NMR(DMSO)δ(ppm): 11.62(s, 1H), 9.60(bs, 1H),7.93(d, J=8.1Hz, 2H), 7.39(d, J=8.1Hz, 2H), 6.97(d, J=7.3Hz, 1H),7.15(d, J=7.3Hz, 1H), 6.98-6.94(m, 2H), 6.77(d, J=7.3Hz, 1H), 6.591(dd,J=7.7, 7.7Hz, 1H), 4.89(bs, 2H), 4.13(s, 2H), 2.17 (s, 3H). LRMS:390.1(calc) 391.2(found). 49 219 360

CH CH 4-(5-Benzoylamino-4-cyano-3- methyl-thiophen-2-ylmethyl)-N-(2-amino-phenyl)-benzamide 1H NMR(DMSO)δ(ppm): 11.77(s, 1H), 9.61(s,1H); 7.93(d, J=7.0Hz, 4H), 7.52-7.63(m, 3H), 7.38(d, J= 7.6Hz, 2H),7.16(d, J=7.6Hz, 1H), 6.96(t, J=7.6Hz, 1H), 6.77(d, J=7.6Hz, 1H),6.59(t, J=7.6Hz, 1H), 4.89(s, 2H), 4.15(s, 2H), 2.24(s, 3H).(MH)⁺: 467.049 220 361

CH CH N-(2-Amino-phenyl)-4-[4-cyano- 3-methyl-5-(3-phenyl-ureido)-thiophen-2-ylmethyl]-benzamide 1H NMR(DMSO)δ(ppm): 10.12(s, 1H), 9.61(s,1H), 9.21(s, 1H); 7.93(d, J=7.6Hz, 2H), 7.27-7.43(m, 6H), 7.16(d,J=7.6Hz, 1H), 6.93-7.05 (m, 2H), 6.77 (d, J=8.2Hz, 1H), 6.59(t, J=7.6Hz,1H), 4.88(s, 2H), 4.08(s, 2H), 2.19(s, 3H).(MH)⁺: 482.4 49 221 362

CH CH N-(2-Amino-phenyl)-4-(3-oxo-2,3- dihydro-benzo[1,4]oxazin-4-ylmethyl)-benzamide ¹H NMR: (DMSO)δ(ppm): 9.60(s, 1H), 7.92(d, J= 8.2Hz,2H), 7.40(d, J=8.0Hz, 2H), 7.13(d, J=6.9 Hz, 1H), 6.92-7.04(m, 5H),6.75(dd, J=8.1Hz, 1.1 Hz, 1H), 6.57(td, J=7.4Hz, 1.4Hz, 1H), 5.24(s,2H), 4.88(bs, 2H); 4.82(s, 2H).(MH)⁺: 374.1 11 222 363

CH CH N-(2-Amino-phenyl)-4-(3-oxo- 2,3-dihydro-benzo[1,4]thiazin-4-ylmethyl)-benzamide ¹H NMR: (DMSO)δ(ppm): 9.58(s, 1H), 7.90(d, J=8.2Hz, 2H), 7.42(dd, J=8.0Hz, J=1.4Hz, 1H), 7.32(d, J=8.2Hz, 2H),7.19-7.11(m, 3H), 7.04-6.92 (m, 2H), 6.75(dd, J=8.0Hz, 1.4Hz, 1H),6.57(td, J=8.0Hz, 1.6 Hz, 1H), 5.31(s, 2H); 4.88(bs, 2H); 3.70 (s,2H).(MH)⁺: 390.1 11 223 364

CH CH N-(2-Amino-phenyl)-4-(3-oxo-2,3- dihydro-pyrido[3,2-b][1,4]oxazin-4-ylmethyl)-benzamide ¹H NMR: (DMSO)δ(ppm): 9.57(bs, 1H), 7.98(d, J=4.7Hz, 1H), 7.89(d, J=8.2Hz, 2H), 7.45-7.40(m, 3H), 7.15(d, J=8.2Hz,1H), 7.09-7.05 (m, 1H), 6.96 (dd, J=7.6, 7.6Hz, 1H), 6.76(d, J=8.2Hz,1H), 6.58(dd, J=7.6, 7.6Hz, 1H), 5.31(s, 2H), 4.90(bs, 2H), 4.87(s,2H).(MH)⁺: 375.1 11 224 365

CH CH N-(2-Amino-phenyl)-4-(1-hydroxy- 3-oxo-indan-2-ylmethyl)-benzamide ¹H NMR: (DMSO)δ(ppm): 9.67(s, 1H); 7.98(d, J= 8.2Hz, 2H),7.73-7.84(m, 3H), 7.53-7.62(m, 3H), 7.24(d, J=7.6Hz, 1H), 7.04(t,J=7.6Hz, 1H), 6.85 (d, J=8.2Hz, 1H), 6.67(t, J=7.6Hz, 1H), 5.68(d, J=7.0Hz, 1H), 5.27(t, J=6.4Hz, 1H), 4.95(s, 2H), 3.21-3.30(m, 1H),3.11-3.13(m, 2H).(MH)⁺: 373.1 46 225 366

CH CH N-(2-Amino-phenyl)-4- phenoxy-benzamide ¹H NMR: (DMSO)δ(ppm):9.61(s, 1H); 8.01(d, J= 8.8Hz, 2H), 7.45(t, J=7.6Hz, 2H), 7.06-7.24(m,6H), 6.97(t, J=1.6Hz, 1H), 6.78(d, J=7.4Hz, 1H), 6.59(t, J=7.6Hz, 1H),4.88(s, 2H).(MH)⁺: 305.0  1 226 367

CH CH N-(2-Amino-phenyl)-4-[5-(4- methoxy-phenyl)-2,5-dihydro-furan-2-yl]-benzamide ¹H NMR(CDCl₃)δ(ppm): 8.77(s,1H), 7.93(d, J=8.1 Hz,2H), 7.42(d, J=8.4Hz, 2H), 7.38-6.98(m, 6H), 6.91(d, J=8.4Hz, 2H),6.09-5.98(m, 4H), 3.81(s, 3H). 52 230 371

CH CH N-(2-Amino-phenyl)-4-[1,3-bis- (3,4-dimethoxy-phenyl)-ureidomethyl]-benzamide ¹H NMR(DMSO-d₆): δ10.08(brs, 1H), 7.99(d, J=7.9Hz, 2H), 7.70(s, 1H), 7.49(d, J=8.35Hz, 4H), 7.39-7.33(m, 1H),7.30-6.90(m, 7H), 6.87(dd, J= 2.2, 8.35Hz, 1H), 6.78(dd, J=2.2, 8.35Hz,1H), 5.01(s, 2H), 3.80(s, 3H), 3.77(s, 3H), 3.75(s, 6H). 57 231 372

CH CH N-(2-Amino-phenyl)-4-[3-(4- chloro-phenyl)-1-(3,4-dimethoxy-phenyl)-ureidomethyl]-benzamide ¹H NMR(CDCl₃): δ8.02(brs, 1H), 7.90(d,J=7.9Hz, 2H), 7.46(d, J=7.5Hz, 2H), 7.42-7.24(m, 6H), 7.16(t, J=7.5Hz,1H), 6.91(brd, J=5.71Hz, 3H), 6.75 (brd, J=8.3Hz, 1H), 6.70(d, J=1.8Hz,1H), 4.99(s, 1H), 3.97(s, 3H), 3.86(s, 3H). 57 232 373

CH CH N-(2-Amino-phenyl)-4-[1-(3,4- dimethoxy-phenyl)-3-phenyl-ureidomethyl]-benzamide ¹H NMR(DMSO-d₆): δ10.10(brs, 1H), 7.99(d, J=7.9Hz, 2H), 7.88(s, 1H), 7.80-7.72(m, 1H), 7.50(dd, J=7.0, 5.7Hz, 4H),7.37(d, J=7.9 Hz, 1H), 7.30-6.94 (m, 7H), 6.78(d, J=6.6Hz, 1H), 5.03(s,2H), 3.80 (s, 3H), 3.78(s, 3H). 57 233 374

CH CH N-(2-Amino-phenyl)-4-[1-(3,4- dimethoxy-phenyl)-3-(4-phenoxy-phenyl)-ureidomethyl]-benzamide ¹H NMR(CDCl₃): δ8.02(brs, 1H), 7.92(d,J=7.9Hz, 2H), 7.49(d, J=8.35Hz, 2H), 7.43-7.32(m, 5H), 7.10-7.30(2m,5H), 7.19-7.10(m, 2H), 7.01(dd, J= 8.35, 2.2Hz, 3H), 6.94(d, J=7.5Hz,1H), 6.92(d, J= 8.8Hz, 1H), 6.77(dd, J=8.8, 2.2Hz, 1H), 6.72(d, J=2.2Hz,1H), 6.34(s, 2H), 5.02(s, 2H), 3.98(s, 3H), 3.87(s, 3H). 57 234 375

CH CH Biphenyl-4,4′-dicarboxylic acid bis-[(2-amino-phenyl)-amide] ¹HNMR(CD₃OD)δ(ppm): 9.80(bs, 2H), 8.16(d, J=7.9Hz, 4H), 7.96(d, J=7.9Hz,4H), 7.23(d, J=7.4 Hz, 2H), 7.03(dd, J=6.9, 7.4Hz, 2H), 6.84(d, J=8.2Hz, 2H), 6.66(dd, J=6.9, 7.7Hz, 2H), 5.06(bs, 4H). 15 236 377

CH CH N-(2-Amino-phenyl)-4-(pyrimidin- 2-ylaminomethyl)-benzamide¹H-NMR(DMSO-d6),δ(ppm): 9.6(bs, 1H), 8.32(d, J=4.9Hz, 2H), 7.97(dt,J=7.9, 9.9Hz, 2H), 7.85-7.83 (m, 1H), 7.47,(d, J=8.2Hz, 2H), 7.20(d,J=7.9Hz, 1H), 7.01(dt, J=7.4, 7.7Hz, 1H), 6.82(d, J=7.9Hz, 1H),6.66-6.62(m, 1H), 4.98(bs, 2H), 4.61(d, 2H). 13 237 378

CH CH N-(2-Amino-phenyl)-4-(4,6- dimethyl-pyrimidin-2-ylsulfanyl-methyl)-benzamide ¹H-NMR(DMSO-d6),δ(ppm): 9.66(bs, 1H), 7.96(d, J=7.9Hz,2H), 7.61(d, J=7.9Hz, 2H), 7.21(d, J=7.9 Hz, 1H), 7.04-6.99(m, 2H),6.82(d, J=7.9Hz, 1H), 6.64(t, J=7.4Hz, 1H), 4.49(s, 2H), 2.42(s, 6H). 11238 379

CH CH N-(2-Amino-phenyl)-4-(4- trifluoromethyl-pyrimidin-2-ylsulfanylmethyl)-benzamide ¹H-NMR(DMSO-d6),δ(ppm): 9.66(bs, 1H),9.07(d, J=5.2Hz, 1H), 7.97(d, J=7.4Hz, 2H), 7.78(d, J=4.7 Hz, 1H),7.63(d, J=7.4Hz, 2H), 7.19(d, J=7.7Hz, 1H), 7.01(dt, J=7.4, 7.7Hz, 1H),6.81(d, J=8.2Hz, 1H), 6.64(dt, J=7.1, 7.4Hz, 1H), 4.94(bs, 2H), 4.57(s,2H). 11 239 380

N CH Pyridine-2,5-dicarboxylic acid bis-[(2-amino-phenyl)-amide]¹H-NMR(DMSO-d6),δ(ppm): 10.23(bs, 1H), 10.04 (bs, 1H), 9.30(s, 1H),8.62(dd, J=1.8, 8.0Hz, 1H), 8.30(d, J=8.1Hz, 1H), 7.55(d, J=7.4Hz, 1H),7.24 (d, J=7.4Hz, 1H), 7.04(dd, J=7.0, 14.0Hz, 2H), 6.90-6.83(m, 2H),6.74-6.63(m, 2H), 5.11(bs, 4H). 1 240 381

CH CH N-(2-Amino-phenyl)-4-(pyridin- 2-ylsulfanylmethyl)-benzamide¹H-NMR(DMSO-d6),δ(ppm): 9.66(bs, 1H), 8.52(bs, 1H), 7.96(d, J=7.4Hz,2H), 7.69(d, J=5.8Hz, 1H), 7.59(d, J=7.4Hz, 2H), 7.38(d, J=7.7Hz, 1H),7.19(bs, 2H), 7.00 (d, J=6.9Hz, 1H), 6.83(d, J=6.9Hz, 1H), 6.64(dd,J=6.7, 7.2Hz, 1H), 4.94(bs, 2H), 4.55 (b+s, 2H). 11 241 382

CH CH N-(2-Amino-phenyl)-4-[(4,6- dimethyl-pyrimidin-2-ylamino)-methyl]-benzamide ¹H-NMR(DMSO-d6),δ(ppm): 9.65(bs, 1H), 7.96(d, J=7.9Hz,2H),7.57(d, J=6.3Hz, 1H), 7.47(d, J=7.7 Hz, 2H), 7.21(d, J=7.4Hz, 1H),7.00(d, J=5.8Hz, 1H), 6.59(d, J=6.6Hz, 1H), 6.64(dd, J=6.0, 7.4Hz, 1H),5.01(s, 2H), 4.61(d, J=6.0Hz, 2H), 2.24(s, 6H). 33 242 383

CH CH N-(2-Amino-phenyl)-4-[(4,6- dimethyl-pyridin-2-ylamino)-methyl]-benzamide ¹H-NMR(DMSO-d6),δ(ppm): 9.66(bs, 1H), 7.98(d, J=7.9Hz,2H), 7.50(d, J=8.2Hz, 2H), 7.96(d, J=7.9 Hz, 1H), 7.01(dd, J=7.7, 7.4Hz,1H), 6.82 (d, J=7.9 Hz, 1H), 6.64(t, J=7.4Hz, 1H), 6.33(s, 1H), 6.25(s,1H), 4.58(d, J=4.4Hz, 2H), 2.28(s, 3H), 2.17(s, 3H). 33 243 384

CH CH N-(2-Amino-phenyl)-4-(4,6- dimethyl-pyrimidin-2-yloxymethyl)-benzamide ¹H-NMR(DMSO-d6),δ(ppm): 9.58(bs, 1H), 7.88(d,J=5.8Hz, 2H),7.46(d, J=8.2Hz, 2H), 6.90-6.81(m, 1H), 6.68(d, J=7.9Hz,1H), 6.50(t, J=7.4 Hz, 1H), 6.40-6.38(m, 1H), 6.29-6.26(m, 1H), 5.33(s,2H), 2.25(s, 6H). 11 244 385

CH CH N-(2-Amino-phenyl)-4-[(6- methoxy-pyrimidin-4-ylamino)-methyl]-benzamide ¹H-NMR(DMSO-d6),δ(ppm): 9.64(bs, 1H), 8.21(bs, 1H),7.95(d, J=7.96Hz, 2H), 7.83(d, J=5.8Hz, 1H), 7.44(d, J=7.9Hz, 2H),7.19(d, J=7.7Hz, 1H), 7.00(dd, J=7.4, 7.7Hz, 1H), 6.80(d, J=7.9Hz, 1H),6.64(d, J=7.1Hz, 1H), 4.96(bs, 2H), 4.58(bs, 2H), 3.81(s, 3H). 33 245386

CH CH 4-[(6-Acetyl-benzo[1,3]dioxol- 5-ylamino)-methyl]-N-(2-amino-phenyl)-benzamide ¹H-NMR(DMSO-d6),δ(ppm): 9.79(bs, 1H), 7.99(d, J=8.5Hz,2H), 7.48(d, J=7.96Hz, 2H), 7.39(bs, 1H), 7.21(d, J=7.4Hz, 1H), 7.02(dd, J=7.1, 7.7Hz, 1H), 6.83(d, J=7.7Hz, 1H), 6.64(t, J=7.4Hz, 1H), 6.36(bs, 1H), 6.00(d, J=2.2Hz, 2H), 4.59(bs, 2H), 2.52 (bs, 3H). 33 246 387

CH CH N-(2-Amino-phenyl)-4-[(4-chloro- 6-methoxy-pyrimidin-2-ylamino)-methyl]-benzamide ¹H-NMR(DMSO-d6),δ(ppm): 9.66(bs, 1H), 7.96(d, J=7.9Hz,2H), 7.47(bs, 2H), 7.39(bs, 1H), 7.19(d, J=7.4Hz, 1H), 7.00(dd, J=6.9,7.4Hz, 1H), 6.81(d, J=7.1Hz, 1H), 6.63(dd, J=7.7, 6.8Hz, 1H), 6.10(bs,1H), 4.56(d, J=6.0Hz,, 2H), 3.83(s, 3H). 33 247 388

CH CH N-(2-Amino-phenyl)-4-[(2,6- dimethoxy-pyridin-3-ylamino)-methyl]-benzamide ¹H-NMR(DMSO-d6),δ(ppm): 9.63(bs, 1H), 7.94(d, J=6.9Hz,2H), 7.47(d, J=6.59Hz, 2H), 7.15(d, J= 7.9Hz, 1H), 6.99(dd, J=5.7,7.4Hz, 1H), 6.80(d, J= 7.8Hz, 1H), 6.71(d, J=6.6Hz, 1H), 6.62(dd, J=7.7,7.1Hz, 1H), 6.15(d, J=8.2Hz, 1H), 4.96(bs, 2H), 4.38(bs, 2H), 3.94(s,3H), 3.75(s, 3H). 33 248 389

CH CH N-(2-Amino-phenyl)-4-[(1H- benzoimidazol-2-ylamino)-methyl]-benzamide ¹H-NMR(DMSO-d6),δ(ppm): 10.9(bs, 1H), 9.64(bs, 1H),7.99(bs, 2H), 7.55(bs, 2H), 7.21-7.17(m, 3H), 7.14-6.81(m, 4H), 6.64(d,J=6.0Hz, 1H), 4.92(bs, 2H), 4.65(bs, 2H). 33 249 390

CH CH N-(2-Amino-phenyl)-4-[(6- methoxy-pyridin-2-ylamino)-methyl]-benzamide ¹H-NMR(DMSO-d6),δ(ppm): 9.60(bs, 1H), 7.96(d, J=7.9Hz,1H), 7.52-7.50(m, 2H), 7.37-7.30(m, 1H), 7.25-7.21(m, 2H), 7.19-6.99(m,1H), 6.84-6.81 (m, 1H), 6.67-6.64(m, 1H), 6.11-6.07(m, 1H), 5.93-5.89(m, 1H), 4.93(bs, 2H), 4.56(d, J=5.8Hz, 2H), 3.80(s, 3H). 37 250 391

CH CH N-(2-Amino-phenyl)-4-(quinolin- 8-ylsulfanylmethyl)-benzamide¹H-NMR(DMSO-d6),δ(ppm): 9.68(bs, 1H), 8.95(bs, 2H), 8.43-8.38(m, 1H),7.90(bs, 2H), 7.80-7.55(m, 6H), 7.22(d, J=7.7Hz, 1H), 7.03(d, J=7.7Hz,1H), 6.63(d, J=7.4Hz, 1H), 5.05(bs, 2H), 4.48(d, J=7.7, 2H). 11 251 392

CH CH N-(2-Amino-phenyl)-4-[(2,6- dimethoxy-pyrimidin-4-ylamino)-methyl]-benzamide ¹H-NMR(DMSO-d6),δ(ppm): 9.66(bs, 1H), 7.97(d, J=7.9Hz,2H), 7.84(t, J=5.9Hz, 1H), 7.46(d, J=7.46 Hz, 2H), 7.20(d, J=7.9Hz, 1H),7.04 (d, J=6.6Hz, 1H), 6.83(d, J=7.9Hz, 1H), 6.64(dd, J=7.7, 7.4Hz, 1H),5.51(bs, 1H), 4.57(bs,, 2H), 3.82(s, 3H), 3.84(s, 3H). 37 252 393

CH CH N-(2-Amino-phenyl)-4-(3,5- dimethoxy-benzylamino)- benzamide¹H-NMR(DMSO-d6),δ(ppm): 9.63(bs, 1H), 7.79(d, J=8.5Hz, 2H), 7.19(d,J=6.6Hz, 1H), 7.00(dd, J=7.9, 7.1Hz, 1H), 6.62(t, J=6.0Hz, 1H), 6.82(dd,J=1.4, 7.9 Hz, 1H), 6.67(d, J=8.8Hz, 2H), 6.58(bs, 2H), 6.42 (bs, 1H),4.87(bs, 2H), 4.34(d, J=6.0Hz, 2H), 3.77(s, 6H). 37 253 394

CH CH N-(2-Amino-phenyl)-4-(3- methoxy-phenylsulfanylmethyl)- benzamide¹H-NMR(DMSO-d6),δ(ppm): 9.66(bs, 1H), 7.96(d, J=7.9Hz, 2H), 7.55(d,J=8.2Hz, 2H), 7.29-7.20(m, 2H), 7.02-6.95(m, 2H), 6.84-6.79(m, 1H),6.67-6.62 (m, 1H), 6.57-6.54(m, 1H), 6.44-6.41(m, 1H), 4.93 (bs, 2H),4.41(bs, 2H), 3.79(s, 3H). 11 254 395

CH CH N-(2-Amino-phenyl)-4-(3,5- dimethoxy-phenoxymethyl)- benzamide¹H-NMR(DMSO-d6),δ(ppm): 9.72(bs, 1H), 8.05(d, J=8.2Hz, 2H), 7.61(d,J=7.9Hz, 2H), 7.24(d, J=7.4 Hz, 1H), 7.04(dd, J=6.9, 7.1Hz, 1H), 6.85(d,J=6.9 Hz, 1H), 6.66(dd, J=7.4, 7.7Hz, 1H), 6.27(s, 2H), 6.26(s, 1H),5.23(s, 2H), 5.21(bs, 2H), 3.77(s, 6H). 11 255 396

CH CH N-(2-Amino-phenyl)-4-(quinolin- 2-yloxymethyl)-benzamide¹H-NMR(DMSO-d6),δ(ppm): 9.70(bs, 1H), 8.35(d, J=9.1Hz, 2H), 8.05(d,J=7.9Hz, 2H), 7.96(d, J=7.9 Hz, 1H), 7.85(d, J=8.2Hz, 1H), 7.76-7.69(m,2H), 7.51(dd, J=6.9, 7.1Hz, 1H), 7.24-7.16(m, 2H), 7.02 (dd, J=6.9,7.4Hz, 1H), 6.83(d, J=8.2Hz, 1H), 6.66 (d, J=7.4Hz, 1H), 5.66(s, 2H),4.94(bs, 2H). 11 256 397

CH CH N-(2-Amino-phenyl)-4-[(3,5- dimethoxy-phenylamino)-methyl]-benzamide ¹H-NMR(DMSO-d6),δ(ppm): 9.62(bs, 1H), 7.96(d, J=7.9Hz,2H), 7.49(d, J=7.9Hz, 2H), 7.19(d, J=7.9 Hz, 1H), 7.00(dd, J=7.5, 7.9Hz,1H), 6.81(d, J=7.9 Hz, 1H), 6.63(dd, J=7.0, 8.0Hz, 1H), 5.78(s, 2H),5.76(s, 1H), 4.92(bs,, 2H), 4.35(d, J=5.7, 2H), 3.65 (s, 6H). 33 257 398

CH N bis(N-(2-Amino-phenyl)- nicotinamide)-6-disulfide¹H-NMR(DMSO-d6),δ(ppm): 9.82(bs, 2H), 9.08(bs, 2H), 8.34(d, J=8.3Hz,2H), 7.83(d, J=8.3Hz, 2H), 7.18(d, J=7.5Hz, 2H), 7.01(dd, J=6.3, 7.0Hz,2H), 6.80(d, J=7.9Hz, 2H), 6.61(t, J=7.03Hz, 2H), 5.05 (bs, 4H).  1 258399

CH CH N-(2-Amino-phenyl)-4- (isoquinolin-1-ylaminomethyl)- benzamide¹H-NMR(DMSO-d6),δ(ppm): 9.90(bs, 1H), 8.16(bs, 2H), 7.65(d, J=4.8Hz,2H), 7.54(bs, 2H), 7.25(d, J=7.0Hz, 2H), 7.11(bs, 2H), 7.07-7.02(m, 2H),6.84 (d, J=7.9Hz, 1H), 6.67(bs, 1H), 5.01(bs, 2H), 4.88 (bs, 2H). 33 259400

CH CH N-(2-Amino-phenyl)-4-[(2,3- dihydro-benzo[1,4]dioxin-6-ylamino)-methyl]-benzamide ¹H-NMR(DMSO-d6),δ(ppm): 9.66(bs, 1H), 7.97(d,J=7.0Hz, 2H), 7.51(d, J=7.0Hz, 2H), 7.22(d, J=7.5 Hz, 1H), 7.02-6.97(m,1H), 6.84(bs, 1H), 6.82-6.71 (m, 2H), 6.16(d, J=6.6Hz, 1H), 6.08(s, 1H),4.32(bs, 2H), 4.16-4.13(m, 4H). 33 260 401

CH CH 4-[(4-Acetylamino-phenylamino)- methyl]-N-(2-amino-phenyl)-benzamide ¹H-NMR(DMSO-d6),δ(ppm): 9.66(bs, 1H), 9.56(bs, 1H), 7.97(d,J=7.9Hz, 2H), 7.53(d, J=7.9Hz, 2H), 7.28(d, J=8.8Hz, 2H), 7.22(d,J=7.9Hz, 1H), 7.02(t, J=7.5Hz, 1H), 6.83(d, J=7.9Hz, 1H), 6.65(t, J=7.5Hz, 1H), 6.55(d, J=8.3Hz, 2H), 4.98(bs, 2H), 4.38 (bs, 2H), 2.00(s, 3H).33 261 402

CH CH N-(2-Amino-phenyl)-4-[(4- morpholin-4-yl-phenylamino)-methyl]-benzamide ¹H-NMR(DMSO-d6),δ(ppm): 9.65(bs, 1H), 7.98(d, J=7.9Hz,2H), 7.52(d, J=7.9Hz, 2H), 7.21(d, J=7.5 Hz, 1H), 7.02(dd, J=7.0, 7.9Hz,1H), 6.83(d, J=7.9 Hz, 1H), 6.78(d, J=8.8Hz, 2H), 6.64(t, J=7.5Hz, 1H),6.55(d, J=8.8Hz, 2H), 4.94(bs, 2H), 4.35(d, J=5.7 Hz, 2H), 3.74(t,J=4.4Hz, 4H), 2.92(t, J=4.4Hz, 4H). 33 262 403

CH CH N-(2-Amino-phenyl)-4-[(4- methoxy-2-methyl-phenylamino)-methyl]-benzamide ¹H-NMR(DMSO-d6),δ(ppm): 9.64(bs, 1H), 7.96(d, J=7.6Hz,2H), 7.52(d, J=7.6Hz, 2H), 7.21(d, J=8.2 Hz, 1H), 7.02(t, J=8.2, 7.0Hz,1H), 6.83(d, J=8.2Hz, 1H), 6.71-6.53(m, 3H), 6.32-6.30(m, 1H), 4.94(bs,2H), 4.45(d, J=5.9Hz, 2H), 3.65(s, 3H), 2.23(s, 3H). 33 263 404

CH CH N-(2-Amino-phenyl)-4-[(2-cyano- 4-methoxy-phenylamino)-methyl]-benzamide ¹H-NMR(DMSO-d6),δ(ppm): 9.65(bs, 1H), 7.98(d, J=7.4Hz, 2H),7.56(d, J=7.5Hz, 2H), 7.19(d, J=7.9 Hz, 1H), 6.99(d, J=7.5Hz, 1H),6.82(d, J=7.9Hz, 1H), 6.63(t, J=6.6Hz, 2H), 6.27(s, 1H), 4.93(bs, 2H),4.55(d, J=5.3Hz, 2H), 3.69(s, 6H). 33 264 405

CH CH N-(2-Amino-phenyl)-4-{[4- methoxy-3-(pyridin-3-ylmethoxy)-phenylamino]-methyl}-benzamide ¹H-NMR(DMSO-d6),δ(ppm): 9.62(s, 1H),8.72(s, 1H), 8.49(d, J=10.1Hz, 1H), 7.93(d, J=7.9Hz, 2H), 7.68 (d,J=6.6Hz, 1H), 7.37(d, J=7.5Hz, 2H), 7.16 (d, J=7.5Hz, 1H), 6.97(t,J=7.5Hz, 1H), 6.78(d, J= 7.9Hz, 1H), 6.69(d, J=8.8Hz, 1H), 6.62(d, J=7.5Hz, 1H), 6.23(d, J=2.6Hz, 1H), 6.09(J=8.8Hz, 1H), 5.76(s, 1H), 4.64(bs,4H), 3.62(s, 3H). 33 265 406

CH CH 2-[4-(2-Amino-phenylcarbamoyl)- benzylamino]-4,5-dimethoxy-benzoic acid ¹H-NMR(DMSO-d6),δ(ppm): 9.67(bs, 1H), 8.00(d, J=7.9Hz, 2H),7.54(d, J=7.9Hz, 2H), 7.34 (s, 1H), 7.20(d, J=7.9Hz, 2H), 7.0(t,J=7.9Hz, 1H), 6.82(d, J=7.9Hz, 1H), 6.62(t, J=7.9Hz, 1H), 6.31(s, 1H),4.95(bs, 2H), 4.62(bs, 2H), 3.75(s, 3H), 3.70(s, 3H). 33 266 407

CH CH N-(2-Amino-phenyl)-4-[(3,5- dimethyl-phenylamino)-methyl]-benzamide ¹H-NMR(DMSO-d6),δ(ppm): 9.60(s, 1H), 7.93(d, J=7.9Hz, 2H),7.45(d, J=7.9Hz, 2H), 7.16(d, J=7.5 Hz, 1H), 6.97(t, J=7.5Hz, 1H),6.78(d, J=7.9Hz, 1H), 6.58(t, J=7.0Hz, 1H), 6.19-6.17(m, 3H), 4.88 (s,2H), 4.32(d, J=5.7Hz, 2H), 2.10(s, 6H). 33 267 408

CH CH N-(2-Amino-phenyl)-4-{[4- (pyridin-3-ylmethoxy)-phenylamino]-methyl}-benzamide ¹H-NMR(DMSO-d6),δ(ppm): 9.65(s, 1H),8.72(s, 1H), 8.54(s, 1H), 8.49(d, J=10.9Hz, 1H), 7.97(d, J=7.9Hz, 2H),7.71(d, J=7.9Hz, 1H), 7.44(d, J=8.3 Hz, 2H), 7.41-7.36(m, 1H), 7.20(d,J=7.9Hz, 1H), 7.00(t, J=7.4Hz, 1H), 6.83(d, J=7.0Hz, 1H), 6.70- 6.60(m,4H), 4.62(s, 4H). 33 268 409

CH CH N-(2-Amino-phenyl)-4-[(2,4- dimethyl-phenylamino)-methyl]-benzamide ¹H-NMR(DMSO-d6),δ(ppm): 9.58(s, 1H), 7.90(d, J=7.9Hz, 2H),7.45(d, J=7.5Hz, 2H), 7.15(d, J=7.5 Hz, 1H), 6.96(t, J=7.5Hz, 1H),6.79(s, 1H), 6.76 (d, J=9.6Hz, 1H), 6.68(d, J=7.9Hz, 1H), 6.59(t, J=7.0Hz, 1H), 6.22(d, J=7.9Hz, 1H), 4.89(bs, 2H), 4.39(d, J=5.7Hz, 2H),2.15(s, 3H), 2.10(s, 3H). 33 269 410

CH CH N-(2-Amino-phenyl)-4-[(2,4,6- trimethyl-phenylamino)-methyl]-benzamide ¹H-NMR(CD₃OD),δ(ppm): 7.91(d, J=7.9Hz, 2H), 7.43(d, J=8.5Hz,2H), 7.18(d, J=7.5Hz, 1H), 7.08(t, J=7.5Hz, 1H), 6.92(d, J=7.9Hz, 1H),6.77(s, 3H), 4.15(bs, 2H), 2.19(s, 9H). 33 270 411

CH CH N-(2-Amino-phenyl)-4-[(4-chloro- 6-morpholin-4-yl-pyrimidin-2-ylamino)-methyl]-benzamide ¹H NMR(300 MHz, DMSO-D6)δ***(ππ[2 ): 9.66(s,1H), 7.97(d, J=8.0Hz, 2H), 7.82(m, 1H), 7.47(d, J= 7.7Hz, 2H), 7.21(d,J=8.2Hz, 1H), 7.03(dd, J= 7.1, 7.1Hz, 1H), 6.84(d, J=7.7Hz, 1H),6.65(dd, J= 7.4, 7.4Hz, 1H), 6.17(bs, 1H), 4.94(s, 2H, NH₂), 4.53(d,J=5.8Hz, 2H), 3.58(m, 4H), 3.62(m, 4H). 24, 33 271 412

CH CH N-(2-Amino-phenyl)-4-(3,4,5- trimethoxy-benzylamino)- benzamide ¹HNMR(300 MHz, DMSO-d₆)δ(ppm): 9.33(s, 1H), 7.81(d, J=8.8Hz, 2H), 7.19(d,J=7.7Hz, 1H), 6.99 (m, 1H), 6.87(dd, J=6.0, 5.8Hz, 1H), 6.82(m, 1H),6.77(s, 2H), 6.71(d, J=8.8Hz, 2H), 6.64(m, 1H), 4.87(s, 2H, NH₂),4.32(d, J=5.5Hz, 2H), 3.81(s, 6H), 3.79(s, 3H). 33 272 413

CH CH N-(2-Amino-phenyl)-4-(4-fluoro- benzylamino)-benzamide ¹H NMR(300MHz, DMSO-d₆)δδ (ppm): 9.31(s, 1H), 7.79(d, J=8.7Hz, 2H), 7.45(dd,J=5.8, 8.5Hz, 2H), 7.21(m, 3H), 6.91(m, 2H), 6.81(dd, J=1.1, 8.0Hz, 1H),6.67(d, J=8.8Hz, 2H), 6.62(dd, J=1.0, 7.2Hz, 1H), 4.86(s, 2H, NH₂),4.39(d, J=6.0Hz, 2H). 33 273 414

CH CH N-(2-Amino-phenyl)-4-(4- methoxy-benzylamino)-benzamide ¹H NMR(300MHz, DMSO-d₆)δ(ppm): 9.31(s, 1H), 7.79(dd, J=1.1, 8.5Hz, 2H), 7.33(d,J=7.1Hz, 2H), 7.19(d, J=7.7Hz, 1H), 6.97(m, 3H), 6.84(m, 2H), 6.65(m,3H), 4.86(s, 2H, NH₂), 4.33(d, J=5.5 Hz, 2H), 3.58(d, J=1.6Hz, 3H). 33274 415

CH CH N-(2-Amino-phenyl)-4-[(4-fluoro- phenylamino)-methyl]-benzamide ¹HNMR(300 MHz, DMSO-d₆)δ(ppm): 9.66(s, 1H), 7.99(d, J=7.9Hz, 2H), 7.53(d,J=8.0Hz, 2H), 7.21 (d, J=8.0Hz, 1H), 7.02(ddd J=1.6, 7.1, 8.2Hz, 1H),6.93(dd, J=8.8, 9Hz, 2H), 6.83(dd, J=1.1, 8.0Hz, 1H), 6.63(m, 3H),6.35(t, J=6.2Hz, 1H), 4.94(s, 2H, NH₂), 4.38(d, J=6.3Hz, 2H). 33 275 416

CH CH N-(2-Amino-phenyl)-4-(3-fluoro- benzylamino)-benzamide ¹H NMR(300MHz, DMSO-d₆)δ(ppm): 9.32(s, 1H), 7.79(d, J=8.8Hz, 2H), 7.44(m, 1H),7.26(m, 1H), 7.18 (dd, J=1.4, 8.0Hz, 2H), 7.12(ddd, J=1.7, 8.0, 8.2Hz,1H), 6.99(m, 2H), 6.81(dd, J=1.4, 8.0Hz, 1H), 6.67 (dd, J=1.6, 8.8Hz,2H), 6.62(dd, J=1.4, 7.4Hz, 1H), 4.87(s, 2H, NH₂), 4.45(d, J=6.0Hz, 2H).33 276 417

CH CH N-(2-Amino-phenyl)-4-[(3-fluoro- phenylamino)-methyl]-benzamide ¹HNMR(300 MHz, DMSO-d₆)δ(ppm): 9.66(s, 1H), 7.99(d, J=8.2Hz, 2H), 7.52(d,J=8.0Hz, 2H), 7.21 (d, J=7.7Hz, 1H), 6.99-7.14(m, 2H), 6.83(d, J=8.0 Hz,1H), 6.76(m, 1H), 6.64(dd, J=7.4, 7.4Hz, 1H), 6.46(d, J=8.2Hz, 1H),6.34(m, 2H), 4.94(s, 2H, NH₂), 4.41(d, J=6.0Hz, 2H). 33 277 418

CH CH N-(2-Amino-phenyl)-4-[(4-chloro- 6-methyl-pyrimidin-2-ylamino)-methyl]-benzamide ¹H NMR(300 MHz, DMSO-D₆)δ(ppm): 9.66(s, 1H), 8.23(m,1H), 7.98(d, J=8.2Hz, 2H), 7.47(d, J=8.5 Hz, 2H), 7.21(d, J=7.7Hz, 1H),7.03(ddd, J=1.5, 7.1, 8.0Hz, 1H), 6.83(dd, J=1.5, 8.1Hz, 1H), 6.65 (m,2H), 4.94(s, 2H, NH₂), 4.61(m, 2H), 2.3 2(s, 3H). 33 278 419

CH CH N-(2-Amino-phenyl)-4-[(4,6- dichloro-pyrimidin-2-ylamino)-methyl]-benzamide ¹H NMR(300 MHz, DMSO-D₆)δ(ppm): 9.69(s, 1H), 8.82(m,1H), 7.99(d, J=8.2Hz, 2H), 7.48(d, J=8.0Hz, 2H), 7.27(d, J=7.7Hz, 1H),7.04(d, J=7.7Hz, 1H), 7.0 (d, J=1.6Hz, 1H), 6.84(d, J=8.2Hz, 1H),6.67(m, 1H), 5.0(bs, 2H, NH₂), 4.60(d, J=6.3Hz, 2H). 33 279 420

CH CH N-(2-Amino-phenyl)-4-({4-chloro- 6-[(pyridin-3-ylmethyl)-amino]-pyrimidin-2-ylamino}-methyl)- benzamide ¹H NMR(300 MHz, DMSO-D₆)δ(ppm):9.87(s, 1H), 8.49(bs, 2H), 7.26-8.02(bm, 8H), 7.22(d, J=8.0Hz, 1H),7.03(dd, J=7.4, 7.4Hz, 1H), 6.84(d, J=8.2 Hz, 1H), 6.66(dd, J=7.1,8.0Hz, 1H), 5.86(bs, 1H), 4.95(s, 2H, NH₂), 4.51(m, 2H). 24, 33 280 421

CH CH N-(2-Amino-phenyl)-4-[(6- methoxy-pyridin-3-ylamino)-methyl]-benzamide ¹H NMR(300 MHz, DMSO-D₆)δ(ppm): 9.66(s, 1H), 7.99(d,J=8.4Hz, 2H), 7.54(d, J=7.9Hz, 2H), 7.50 (d, J=2.6Hz, 1H), 7.21(d,J=7.5Hz, 7.9Hz, 1H), 7.12(dd, J=3.08Hz, 8.79Hz, 1H), 7.02(dd, J=7.0 Hz,7.5Hz, 1H), 6.83(d, J=7.0Hz, 1H), 6.65(m, 2H), 6.15(t, J=6.16Hz, 1H),4.94(s, 2H, NH₂), 4.39 (d, J=6.15Hz, 2H), 3.75(s, 3H). 33 281 422

CH CH N-(2-Amino-phenyl)-4-[(4- trifluoromethoxy-phenylamino)-methyl]-benzamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.66(s, 1H), 7.99(d,J=8.0Hz, 2H), 7.53(d, J=8.2Hz, 2H), 7.21 (d, J=7.7Hz, 1H), 7.09(d,J=9.1Hz, 2H), 7.03(dd, J=7.1, 8.2Hz, 1H), 6.83(d, J=8.0Hz, 1H), 6.71(t,J=6.0Hz, 1H), 6.63-6.67(m, 3H), 4.94(s, 2H, NH₂), 4.42(d, J=6.0Hz, 2H).33 282 423

CH CH N-(2-Amino-phenyl)-4-[(3- trifluoromethoxy-phenylamino)-methyl]-benzamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.67(s, 1H), 8.00(d,J=8.2Hz, 2H), 7.53(d, J=8.2Hz, 2H), 7.19 (m, 2H), 7.03(ddd, J=1.5, 8.0,8.8Hz, 1H), 6.85(m, 2H), 6.63(m, 2H), 6.55(s, 1H), 6.50(m, 1H), 4.94(s,2H, NH₂), 4.44(d, J=6.0Hz, 2H). 33  283a  424b

CH CH N-(2-Amino-phenyl)-4-[(3,4- dimethoxy-phenylamino)-methyl]-benzamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.65(s, 1H), 7.98(d, J=7.9Hz,2H), 7.54(d, J=7.9Hz, 2H), 7.22 (d, J=7.9Hz, 1H), 7.02 (dd, J=7.9Hz,7.9Hz, 1H), 6.83(d, J=7.9Hz, 1H), 6.72(d, J=8.79Hz, 1H), 6.45(dd,J=7.49Hz, 7.49Hz, 1H), 6.39(d, J=2.2 Hz, 1H), 6.01-6.08(m, 2H), 4.94(s,2H, NH₂), 4.36(d, J=6.16Hz, 2H), 3.72(s, 3H), 3.65(s, 3H). 33 284 425

CH CH N-(2-Amino-phenyl)-4-(3- trifluoromethoxy-benzylamino)- benzamide¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.31(s, 1H), 7.80(d, J=8.8Hz, 2H),7.45-7.56(m, 2H), 7.39(s, 1H), 7.29(d, J=7.7Hz, 1H), 7.18(d, J=6.6Hz,1H), 6.96-7.03(m, 2H), 6.81(d, J=6.9Hz, 1H), 6.68(d, J= 8.8Hz, 2H),6.64(d, J=7.7Hz, 1H), 4.86(s, 2H, NH₂), 4.48(d, J=5.8Hz, 2H). 33 285 426

CH CH N-(2-Amino-phenyl)-4-(4- trifluoromethoxy-benzylamino)- benzamide¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.31(s, 1H), 7.79(d, J=8.8Hz, 2H),7.54(d, J=8.8Hz, 2H), 7.39 (d, J=8.0Hz, 2H), 7.18(dd, J=1.4, 7.7Hz, 1H),6.99(ddd, J=1.4, 8.0, 8.5Hz, 2H), 6.81(dd, J=1.4, 8.0, 1H), 6.68(d,J=8.8Hz, 2H), 4.85(s, 2H, NH₂), 4.45(d, J=6.0Hz, 2H). 33 286 427

CH CH N-(2-Amino-phenyl)-4-[(4- methoxy-phenylamino)-methyl]- benzamide¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.64(s, 1H), 7.97(d, J=8.2Hz, 2H),7.53(d, J=8.5Hz, 2H), 7.21 (d, J=1.4, 8.0Hz, 1H), 7.02(ddd, J=1.4, 7.4,8.0Hz, 1H), 6.83(dd, J=1.4, 8.0Hz, 1H), 6.74(m, 2H), 6.65 (ddd, J=1.4,7.7, 8.8Hz, 1H), 6.58(m, 2H), 5.99(t, J=6.3Hz, 1H), 4.93(s, 2H, NH₂),4.36(d, J= 6.0Hz, 2H), 3.68(s, 3H). 33 287 428

CH CH N-(2-Amino-phenyl)-4- (benzo[1,3]dioxol-5-ylaminomethyl)-benzamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.65(s, 1H),7.98(d, J=7.9Hz, 2H), 7.52(d, J=7.9Hz, 2H), 7.21 (d, J=7.5Hz, 1H),7.02(dd, J=7.0, 7.0Hz, 1H), 6.83(d, J=7.5Hz, 1H), 6.63-6.69(m, 2H),6.33(d, J= 2.2Hz, 1H), 6.15(t, J=6.16Hz, 1H), 6.04(dd, J= 2.2, 8.4Hz,1H), 5.86(s, 2H), 4.94(s, 2H, NH₂), 4.35 (d, J=6.16Hz, 2H). 33 288 429

CH CH N-(2-Amino-phenyl)-4-[(2- methoxy-phenylamino)-methyl]- benzamide¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.63(s, 1H), 7.90(d, J=8.2Hz, 2H),7.52(d, J=8.2Hz, 2H), 7.22 (d, J=7.7Hz, 1H), 7.02(ddd, J=1.4, 7.1,8.0Hz, 1H), 6.86(m, 2H), 6.56-6.75(m, 3H), 6.43(dd, J= 1.6, 7.7Hz, 1H),5.75(t, J=6.3Hz, 1H), 4.93(s, 2H, NH₂), 4.47(d, J=6.3Hz, 2H), 3.88(s,3H). 33 289 430

CH CH N-(2-Amino-phenyl)-4-[(3- methoxy-phenylamino)-methyl]- benzamide¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.61(s, 1H), 7.98(d, J=8.0Hz, 2H),7.53(d, J=8.2Hz, 2H), 7.21 (dd, J=1.1, 7.7Hz, 1H), 6.97-7.05(m, 2H),6.82(dd, J=1.2, 8.1Hz, 1H), 6.46(ddd, J=1.4, 7.7, 8.0Hz, 1H), 6.41(t,J=6.3Hz, 1H), 6.16-6.25(m, 3H), 4.93 (s, 2H, NH₂), 4.39(d, J=6.0Hz, 2H),3.69(s, 3H). 33 290 431

CH CH N-(2-Amino-phenyl)-4-(2,2,2- trifluoro-acetylamino)-benzamide ¹HNMR(300 MHz, DMSO-d₆)δ(ppm): 11.53(s, 1H), 9.71(s, 1H), 8.08(d, J=8.2Hz,2H), 7.86(d, J=8.8 Hz, 2H), 7.23(d, J=7.6Hz, 1H), 7.03(dd, J=7.0, 7.6Hz,1H), 6.84(d, J=8.2Hz, 1H), 6.66(dd, J= 7.0, 7.6Hz, 1H), 4.96(s, 2H,NH₂). 14 291 432

CH CH N-(2-Amino-phenyl)-4-{[4-chloro- 6-(3,4,5-trimethoxy-benzylamino)-pyrimidin-2-ylamino]- methyl}-benzamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm):9.64(s, 1H), 7.95(d, J=7.5Hz, 2H), 7.70(bs, 2H), 7.45(d, J= 8.4Hz, 2H),7.22(d, J=7.9Hz, 1H), 7.03(dd, J= 7.0, 7.5Hz, 1H), 6.84(d, J=7.9,Hz,1H), 6.60-6.72 (m, 3H), 5.87(s, 1H), 4.93(s, 2H, NH₂), 4.54(d, J= 6.2Hz,2H), 4.43(bs, 2H), 3.78(s, 6H), 3.68(s, 3H). 24, 33 292 433

CH CH N-(2-Amino-phenyl)-4-{[4-chloro- 6-(3,4,5-trimethoxy-phenylamino)-pyrimidin-2-ylamino]-methyl}- benzamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm):9.65(s, 1H), 9.43(s, 1H), 7.97(m, 3H), 7.46(bs, 2H), 7.21(d, J= 7.5Hz,1H), 7.02(m, 3H), 6.83(d, J=7.0Hz, 1H), 6.65(dd, J=7.5, 7.5Hz, 1H),6.08(s, 1H), 4.93(s, 2H, NH₂), 4.69(bs, 2H), 3.65(s, 9H). 24, 33 293 434

CH CH N-(2-Amino-phenyl)-4-(3,4- dimethoxy-benzylamino)- benzamide ¹HNMR(300 MHz, DMSO-d₆)δ(ppm): 9.31(s, 1H), 7.79(d, J=8.8Hz, 2H), 7.19(d,J=7.9Hz, 2H), 7.04 (s, 1H), 6.92-7.01(m, 3H), 6.80-6.87(m, 2H), 6.69(d,J=8.8Hz, 2H), 6.62(m, 1H), 4.87(s, 2H, NH₂), 4.32 (d, J=5.7Hz, 2H),3.80(s, 3H), 3.78(s, 3H). 33 294 435

CH CH N-(2-Amino-phenyl)-4-[(4- morpholin-4-yl-pyrimidin-2-ylamino)-methyl]-benzamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.64(s, 1H),7.95(d, J=8.4Hz, 2H), 7.87(d, J=7.9Hz, 1H), 7.47(d, J=7.9Hz, 2H),7.31(bs, 1H), 7.21(d, J=7.5, 1H), 7.02 (dd, J=7.9Hz, 1H), 6.83(d,J=7.9Hz, 1H), 6.65(dd, J=7.0, 7.0Hz, 1H), 6.09(d, J=6.2Hz, 1H), 4.94(s,2H, NH₂), 4.54(d, J=5.7Hz, 2H), 3.67(s, 4H), 3.53(s, 4H). 24, 1, 33 295436

CH CH N-(2-Amino-phenyl)-4-{[2-(1H- indol-3-yl)-ethylamino]-methyl}-benzamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 10.82(s, 1H), 9.65(s, 1H),7.98(d, J=8.4Hz, 2H), 7.56(d, J=7.9Hz, 1H), 7.51(d, J=8.4Hz, 2H),7.38(d, J=7.9Hz, 2H), 7.18-7.23(m, 2H), 7.11(dd, J=7.0, 8.0Hz, 1H), 7.01(m, 2H), 6.83(d, J=7.9Hz, 1H), 6.51(dd, J=7.5, 6.6 Hz, 1H), 4.93(s, 2H,NH₂), 3.89(s, 2H), 2.89(m, 4H). 57 296 437

CH CH N-(2-Amino-phenyl)-4-[(4- methylsulfanyl-phenylamino)-methyl]-benzamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.67(s, 1H), 7.99(d,J=7.5Hz, 2H), 7.52(d, J=7.5Hz, 2H), 7.21(d, J=7.5Hz, 1H), 7.13(d,J=7.5Hz, 2H), 7.03(dd, J=7.5, 7.5Hz, 1H), 6.83(d, J=7.9Hz, 1H), 6.53(m,4H), 4.95 (s, 2H, NH₂), 4.41(d. J=5.7Hz, 2H), 2.37(s, 3H). 33 297 438

CH CH N-(2-Amino-phenyl)-4-[(3- methylsulfanyl-phenylamino)-methyl]-benzamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.66(s, 1H), 7.99(d,J=7.5Hz, 2H), 7.53(d, J=7.5Hz, 2H), 7.21(d, J=7.5Hz, 1H), 7.03(m, 2H),6.83(d, J=7.9Hz, 1H), 6.65(dd, J=7.5, 7.5Hz, 1H), 6.39-6.51(m, 4H),4.94(s, 2H, NH₂), 4.41(d. J=5.7Hz, 2H), 2.42(s, 3H). 33 298 439

CH CH N-(2-Amino-phenyl)-4-{[4-chloro- 6-(3,4-dimethoxy-phenyl)-pyrimidin-2-ylamino]-methyl}- benzamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm):9.66(s, 1H), 8.37(s, 1H), 7.99(d, J=7.5Hz, 2H), 7.68-7.79(m, 2H),7.55(bs, 2H), 7.37(s, 1H), 7.20(d, J=7.1Hz, 1H), 7.11 (bs, 1H), 7.02(dd,J=7.5, 7.5Hz, 1H), 6.82 (d, J=7.9Hz, 1H), 6.64(dd, J=7.5, 7.5Hz, 1H),4.93(s, 2H, NH₂), 4.86(s, 2H), 3.88(s, 6H). 15, 33 299 440

CH CH N-(2-Amino-phenyl)-4-{[4-(3,4- dimethoxy-phenyl)-pyrimidin-2-ylamino]-methyl}-benzamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.64(s, 1H),8.35(d, J=4.8Hz, 1H), 7.97(d, J=7.9Hz, 2H), 7.89 (m, 1H), 7.72(m, 2H),7.55(d, J=7.5Hz, 2H), 7.2 (d, J=5.3Hz, 2H), 7.10(d, J=8.4Hz, 1H),7.01(m, 1H), 6.82(d, J=7.0Hz, 1H), 6.41(t, J=7.5Hz, 1H), 4.92 (s, 2H,NH₂), 4.68(d, J=6.2Hz, 2H), 3.82(s, 6H). 15, 1, 33 300 441

CH CH 4-[(2-Acetyl-4,5-dimethoxy- phenylamino)-methyl]-N-(2-amino-phenyl)-benzamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.68(s, 1H),9.45(t, J=5.7Hz, 1H), 8.01(d, J=7.9Hz, 2H), 7.54 (d, J=8.4Hz, 2H),7.32(s, 1H), 7.21(d, J=7.5Hz, 1H), 7.02(dd, J=6.6, 7.5Hz, 1H), 6.83(d,J=7.5 Hz, 1H), 6.65(dd, J=7.0, 7.5Hz, 1H), 6.31(s, 1H), 4.95(s, 2H,NH₂), 4.63(d, J=5.7Hz, 2H), 3.78(s, 3H), 3.76(s, 3H). 33 301 442

CH CH N-(2-Amino-phenyl)-4-{[4-(3,4- dimethoxy-phenylamino)-pyrimidin-2-ylamino]-methyl}- benzamide ¹H NMR(300 MHz,CD₃OD+CDCl₃)δ(ppm): 7.99 (d, J=7.9Hz, 2H), 7.80(d, J=6.2Hz, 1H), 7.76(s,1H), 7.52(d, J=8.4Hz, 2H), 7.27(m, 1H), 7.14(m, 1H), 7.05(dd, J=2.2,8.8Hz, 1H), 6.95(d, J=7.9Hz, 1H), 6.88(d, J=8.8Hz, 1H), 6.83(d, J=7.9Hz,1H), 6.08(d, J=6.2Hz, 1H), 4.75(s, 2H), 3.79(s, 3H), 3.42(s, 3H). 1, 33302 443

CH CH N-(2-Amino-phenyl)-4-{[[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]- (3,4-dimethoxy-phenyl)-amino]-methyl}-benzamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.66(s, 1H), 7.96(d,J=8.4Hz, 2H), 7.42(d, J=7.9Hz, 2H), 7.20 (d, J=7.5Hz, 1H), 7.02((dd,J=6.6, 8.4Hz, 1H), 6.83 (d, J=7.0Hz, 1H), 6.77(d, J=8.8Hz, 1H), 6.65(dd, J=7.0, 7.0Hz, 1H), 6.44(d, J=2.6Hz, 1H), 6.19(dd, J=2.6, 8.8Hz,1H), 4.93(s, 2H), 4.67(s, 2H), 3.88(t, J=5.7Hz, 2H), 3.71(s, 3H),3.67(s, 3H), 3.60(t, J=5.5Hz), 0.96(s, 9H), 0.06(s, 6H). 33 303 444

CH CH N-(2-Amino-phenyl)-4-{[(3,4- dimethoxy-phenyl)-(2-hydroxy-ethyl)-amino]-methyl}-benzamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm)δ(ppm):9.65 (s, 1H), 7.96(d, J=7.5Hz, 2H), 7.42(d, J=7.5Hz, 2H), 7.21(d,J=7.5Hz, 1H), 7.02((dd, J=7.0, 7.5Hz, 1H), 6.83(d, J=7.9Hz, 1H), 6.78(d,J=8.8Hz, 1H), 6.65(dd, J=7.0, 7.5Hz, 1H), 6.44(s, 1H), 6.19(d, J=8.8Hz,1H), 4.94(s, 2H), 4.79(m, 1H), 4.66(s, 2H), 3.67 and 3.71(2s andbroading underneath, 8H), 3.55(m, 2H). 33, 23 304 445

CH N N-(2-Amino-phenyl)-6-[(3,4,5- trimethoxy-phenylamino)-methyl]-nicotinamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.82(s, 1H), 9.13(s, 1H),8.33(d, J=8.0Hz, 1H), 7.56(d, J=8.5Hz, 1H), 7.21(d, J=7.7Hz, 1H),7.03((dd, J=7.4, 7.7Hz, 1H), 6.82(d, J=8.0Hz, 1H), 6.40(dd, J=7.4,7.7Hz, 1H), 6.31(t, J=5.8Hz, 1H), 5.96(s, 2H), 5.01(s, 2H), 4.48(d,J=5.8Hz, 2H), 3.70(s, 6H), 3.56(s, 3H). 33 305 446

CH N N-(2-Amino-phenyl)-6-[2-(4-oxo- 4H-quinazolin-3-yl)-ethylamino]-nicotinamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 8.69(d, J= 2.2Hz, 1H),8.46(s, 1H), 8.40(d, J=8.8Hz, 1H), 8.32-8.36(m, 1H), 7.91-7.96(m, 1H),7.77(m, 1H), 7.67(m, 1H) 7.5(m, 4H), 7.2(s, 1H), 4.46(t, J=5.9 Hz, 1H),4.09(t, J=5.9Hz, 2H).  3 306 447

CH CH N-(2-Amino-phenyl)-4-[bis- (3-trifluoromethoxy-benzyl)-amino]-benzamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.37(s, 1H), 7.84(dJ=8.8Hz, 2H), 7.54(dd, J=7.9, 7.9Hz, 2H), 7.18-7.37(m, 6H), 7.17(d,J=7.0Hz, 1H), 6.99(dd, J= 7.0, 7.9Hz, 1H), 6.82(m, 3H), 6.63(dd, J=7.5,7.5Hz, 1H), 4.94(s, 4H), 4.86(s, 2H). 33 307 448

CH CH N-(2-Amino-phenyl)-4-[(2- dimethylamino-benzothiazol-5-ylamino)-methyl]-benzamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.58(s, 1H),7.92(d, J=7.9Hz, 2H), 7.49(d, J=7.9Hz, 2H), 7.34(d, J=8.8Hz, 1H),7.15,(d, J=7.5Hz, 1H), 6.96(t, J=7.9Hz, 1H), 6.76(d, J=7.9Hz, 1H), 6.59(d, J=7.5Hz, 1H), 6.55(s, 1H), 6.44(d, J=8.4Hz, 1H), 6.34(t, J=5.7Hz,1H), 4.88(bs, 2H), 4.37(d, J= 5.7Hz, 2H), 3.06(s, 6H). 33 308 449

CH CH N-(2-Amino-phenyl)-4-[(2-oxo- 2,3-dihydro-1H-benzoimidazol-5-ylamino)-methyl]-benzamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 10.2(s, 1H),10.1(s, 1H), 9.62(s, 1H), 7.94(d, J=7.9Hz, 2H), 7.41(d, J=7.9Hz, 2H),7.15(d, J=7.5 Hz, 1H), 6.96(t, J=7.5Hz, 1H), 6.77(d, J=7.9Hz, 1H), 6.69(d, J=8.4Hz, 1H), 6.59(t, J=7.5Hz, 1H), 6.34(d, J= 8.4Hz, 1H), 6.34(t,J=8.4Hz, 1H), 6.30(s, 1H), 4.89(bs, 2H), 4.72(s, 2H). 33 309 450

CH CH N-(2-Amino-phenyl)-4-[(4- trifluoromethylsulfanyl-phenylamino)-methyl]-benzamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.60(s,1H), 7.94(d, J=7.9Hz, 2H), 7.46(d, J=7.9Hz, 2H), 7.35(d, J=8.4Hz, 2H),7.15(d, J=7.9Hz, 1H), 7.11(d, J=6.2Hz, 1H), 6.97(t, J=7.0Hz, 1H), 6.77(d, J=7.5Hz, 1H), 6.66(d, J=8.4Hz, 2H), 6.60(t, J= 7.9Hz, 1H), 4.88(bs,2H), 4.72(d, J=6.2Hz, 2H). 33 310 451

CH CH N-(2-Amino-phenyl)-4-{[2- (pyridin-3-ylmethylsulfanyl)-1H-benzoimidazol-5-ylamino]- methyl}-benzamide ¹H NMR(300 MHz,CD₃OD)δ(ppm): 8.67(d, J=1.8 Hz, 1H), 8.47(dd, J=1.3, 4.4Hz, 1H), 8.08(s,1H), 8.03(d, J=7.9Hz, 2H), 7.92(d, J=8.4Hz, 1H), 7.87(d, J=7.9Hz, 2H),7.58(d, J=8.4Hz, 1H), 7.36-7.30(m, 3H); 7.20-7.15(m, 1H); 7.08(dt, J=1.3, 8.4Hz, 1H), 6.94(dd, J=1.3, 7.9Hz, 1H), 6.77 (d, J=2.2Hz, 1H),6.74(d, J=2.2Hz, 1H), 6.65(d, J= 1.8Hz, 1H), 4.55(s, 2H); 4.20(bs, 2H);3.36(s, 2H). 33 311 452

CH CH N-(2-Amino-phenyl)-4-{[2- (pyridin-3-ylmethylsulfanyl)-benzooxazol-5-ylamino]-methyl}- benzamide ¹H NMR(300 MHz, CD₃OD)δ(ppm):8.60(s, 1H), 8.36(d, J=4.4Hz, 1H), 7.89(d, J=7.9Hz, 2H), 7.87(m, 1H);7.47(d, J=7.9Hz, 2H), 7.30(t, J=6.6 Hz, 1H), 7.20-7.15(m, 2H); 7.04(t,J=7.5Hz, 1H), 6.87(d, J=7.9Hz, 1H), 6.73(t, J=7.5Hz, 1H), 6.66 (s, 1H);6.61(d, J=8.8Hz, 1H), 4.87(s, 2H); 4.45(s, 2H); 4.37(s, 2H); 3.35(s,2H). 33 312 453

N-(2-Amino-5-trifluoromethyl- phenyl)-4-[(3,4-dimethoxy-phenylamino)-methyl]-benzamide ¹H NMR(300 MHz, CDCl₃)δ(ppm): 8.21(s,1H); 7.90 (d, J=8.4Hz, 2H); 7.54(m, 1H); 7.50(d, J=8.4Hz, 2H);7.41-7.34(m, 2H); 6.87(d, J=8.4Hz, 1H); 7.77(d, J=8.4Hz, 1H); 6.35(d,J=2.2Hz, 1H); 6.20(dd, J=2.2, 8.8Hz, 1H); 4.43(s, 2H); 4.29(s, 2H);3.84(s, 6H). 33 313 454

N-(2-Amino-4,5-difluoro-phenyl)- 4-[(3,4-dimethoxy-phenylamino)-methyl]-benzamide ¹H NMR(300 MHz, CDCl₃)δ(ppm): 8.21(s, 1H); 7.84 (d,J=7.9Hz, 2H); 7.45(d, J=7.9Hz, 2H); 7.20(dd, J=2.6, 8.4Hz, 1H); 6.76(d,J=8.8Hz, 1H); 6.57(dd, J=3.9, 7.9Hz, 1H); 6.32(d, J=2.6Hz, 1H); 6.16(dd, J=2.6, 8.4Hz, 1H); 4.40(s, 2H); 3.82(s, 9H). 33 314 455

CH CH N-(2-Amino-phenyl)-4-[(2-oxo- 2,3-dihydro-benzooxazol-5-ylamino)-methyl]-benzamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.60(s, 1H);7.93(d, J=7.9Hz, 2H); 7.47(d, J=7.9Hz, 2H); 7.16 (d, J=7.5Hz, 1H);6.97(m, 2H); 6.78(d, J=7.5Hz, 1H); 6.59(t, J=7.5Hz, 1H); 6.35(t,J=5.7Hz, 1H); 6.27(m, 2H); 4.88(bs, 2H); 4.34(d, J=6.2Hz, 2H). 33 315456

CH CH N-(2-Amino-phenyl)-4-[(2- methylamino-benzothiazol-5-ylamino)-methyl]-benzamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 7.92(d, J=7.9Hz, 2H), 7.66(d, J=4.4Hz, 1H), 7.49(d, J=7.9 Hz, 2H), 7.26(d,J=8.4Hz, 1H), 7.15(d, J=7.9Hz, 1H), 6.96(d, J=8.4Hz, 1H), 6.59(t,J=7.9Hz, 1H), 6.53(s, 1H), ); 6.40(dd, J=1.3, 8.4Hz, 1H); 6.28(t,J=5.7Hz, 1H), 4.88(bs, 2H), 4.36(d, J=5.7Hz, 2H), 2.85(d, J=4.4Hz, 3H).33 316 457

N-(2,6-Diamino-phenyl)-4-[(3,4- dimethoxy-phenylamino)-methyl]-benzamide ¹H NMR(300 MHz, CDCl₃)δ(ppm): 8.09(s, 1H); 7.88 (d, J=7.5Hz,2H); 7.48(d, J=7.5Hz, 2H); 6.97(d, J= 7.9Hz, 1H); 6.73(d, J=8.4Hz, 2H);6.64(d, J= 7.9Hz, 1H); 6.29(s, 1H); 6.14(d, J=8.4Hz, 1H); 4.39(s, 2H);3.81(s, 3H); 3.80(s, 3H); 3.70(bs, 5H). 33 317 458

CH CH N-(2-Amino-phenyl)-4-{[2- (2-methoxy-ethyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylamino]- methyl}-benzamide ¹H NMR(300 MHz,DMSO-d₆)δ(ppm): 9.61(s, 1H); 7.95(d, J=7.9Hz, 2H); 7.73(t, J=5.7Hz, 1H);7.52 (d, J=8.4Hz, 1H); 7.47(d, J=7.9Hz, 2H); 7.15(d, J=7.9Hz, 1H);6.97(d, J=7.5Hz, 1H); 6.92(bs, 1H); 6.86(d, J=8.4Hz, 1H); 6.77(d,J=7.9Hz, 1H); 6.59(t, J=7.5Hz, 1H); 4.89(bs, 2H); 4.54(d, J= 5.7Hz, 2H);3.65(t, J=5.3Hz, 2H); 3.47(t, J=5.3 Hz, 2H); 3.20(s, 3H); 33 318 459

CH CH N-(2-Amino-phenyl)-4-{(3- spiro[1′,2′]dioxolane-1-methyl-2-oxo-2,3-dihydro-1H-indol-5- ylamino)-methyl}-benzamide ¹H NMR(300 MHz,DMSO-d₆)δ(ppm): 9.59(s, 1H); 7.92(d, J=8.3Hz, 2H); 7.46(d, J=8.3Hz, 2H);7.15(d, J=7.5Hz, 1H); 6.96(t, J=7.0Hz, 1H); 6.78-6.71(m, 3H);6.62-6.54(m, 2H); 6.26(t, J=7.5Hz, 1H); 4.87(s, 2H); 4.36-4.32(m, 4H);4.23-4.19 (m, 2H); 2.98(s, 3H). 33 319 460

CH N N-(2-Amino-phenyl)-6-(2- phenylamino-ethylamino)- nicotinamide ¹HNMR(300 MHz, CD₃OD)δ(ppm): 8.67(d, J=2.2 Hz, 1H), 7.97(dd, J=2.5, 8.9Hz,1H), 7.58(m, 1H); 7.51(m, 1H); 7.15(dd, J=1.1, 7.7Hz, 1H), 7.08(m, 2H);6.89(dd, J=1.4, 8.0Hz, 1H), 6.76(dt, J=4.4, 7.7 Hz, 1H), 6.67(d,J=7.7Hz, 2H), 6.60(m, 2H); 4.87(bs, 2H); 3.60(t, J=6.3Hz, 2H), 3.35(t,J=6.3Hz, 2H). 33 320 461

CH CH N-(2-Amino-phenyl)-4-[(1,3- dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-6-ylamino)- methyl]-benzamide ¹H NMR(300 MHz,DMSO-d₆)δ(ppm): 9.59(s, 1H); 7.92(d, J=7.9Hz, 2H); 7.47(d, J=7.9Hz, 2H);7.22(d, J=8.8Hz, 1H); 7.16-7.09(m, 3H); 6.96(t, J=7.5Hz, 1H); 6.76(d,J=7.9Hz, 1H); 6.65-6.56(m, 2H); 4.87 (s, 2H); 4.42(d, J=5.3Hz, 2H);3.44(s, 3H); 3.26(s, 3H). 33 321 462

CH CH N-(2-Amino-phenyl)-4-[(6-methyl- 6H-indolo[2,3-b]quinoxalin-9-ylamino)-methyl]-benzamide ¹H NMR(300 MHz, DMSO-d₆)δ(ppm): 9.60(s, 1H);8.19(d, J=8.4Hz, 1H); 8.05(d, J=8.4Hz, 1H); 7.95(d, J=7.9Hz, 2H);7.76(t, J=7.0Hz, 1H); 7.65 (t, J=7.9Hz, 1H); 7.57(d, J=7.9Hz, 2H);7.54(d, J= 8.8Hz, 1H); 7.41(d, J=1.3Hz, 1H); 7.22(dd, J= 1.8, 8.8Hz,1H); 7.14(d, J=7.9Hz, 1H); 6.95(t, J= 7.5Hz, 1H); 6.76(t, J=7.9Hz, 1H);6.57(t, J=7.5 Hz, 1H); 6.51(bs, 1H); 4.86(bs, 2H); 4.54(d, J=4.8 Hz,2H); 3.85(s, 3H). 33 322 463

N CH N-(2-Amino-phenyl)-6-(1-hydroxy- cyclohexylethynyl)-nicotinamideLRMS calc: 335.40, found: 336.1(MH)⁺ 14, 3 323 464

N CH N-(2-Amino-phenyl)-6-p- tolylsulfanyl-nicotinamide LRMS calc:335.42, found: 336.1(MH)⁺ 14, 3 324 465

CH CH N-(2-Amino-phenyl)-4-[5-(indan- 2-ylaminomethyl)-thiophen-2-ylmethyl]-benzamide LRMS calc: 453.6, found: 454.2(MH)⁺ 21 325 466

CH CH N-(2-Amino-phenyl)-4-[5-(pyridin- 2-ylaminomethyl)-thiophen-2-ylmethyl]-benzamide LRMS calc: 414.52, found: 415(MH)⁺ 21 326 467

CH CH N-(2-Amino-phenyl)-4-[(5-bromo- thiazol-2-ylamino)-methyl]-benzamide LRMS calc: 403.3, found: 404(MH)⁺ 21 327 468

CH CH N-(2-Amino-phenyl)-4-[(5-phenyl- 1H-pyrazol-3-ylamino)-methyl]-benzamide LRMS calc: 483.45, found: 484.1(MH)⁺ 21

TABLE 4c Characterization of Additional Compounds Ex. Cpd Compound NameCharacterization Schm 426 571

N-(2-Hydroxy-phenyl)-4-[(3,4,5-tri- methoxy-phenyl-amino)-methyl]-benza- mide ¹H NMR(DMSO-d₆): δ9.57(brs, 1H), 7.98(d,J=8.3Hz, 2H), 7.75(d, J=7.5Hz, 1H), 7.57(d, J=8.3Hz, 2H), 7.07(t,J=8.3Hz, 1H), 6.95(d, J=7.0Hz, 1H), 6.85(t, J=7.9Hz, 1H), 6.21(t,J=6.1Hz, 1H), 5.95 (s, 2H), 4.38(d, J=5.7Hz, 2H), 3.70(s, 6H), 3.56(s,3H). 33, 55 427 572

N-(2-hydroxy-phenyl)-4-[(3,4-Di- methoxy-phenyl- amino)-methyl]-benza-mide ¹H NMR(300MHz, DMSO-D₆)δ(ppm): 9.9(bs, 1H), 9.53(s, 1H), 7.97(d,J=7.9Hz, 2H), 7.73(d, J=7.5Hz, 1H), 7.55(d, J=7.9Hz, 2H), 7.08(dd,J=7.5, 7.5Hz, 1H), 6.96(d, J=7.9Hz, 1H), 6.88(dd, J=7.5, 7.5Hz, 1H),6.72(d, J=8.8Hz, 1H), 6.38(s, 1H), 6.05 (m, 2H), 4.36(d, J=5.7Hz, 2H),3.72(s, 3H), 3.65(s, 3H). 33, 55 428 573

N-(4-Amino-thiophen-3-yl)-4-{[6-(2-morpho- lin-4-yl-eth-oxy)-benzothiazol-2-yla- mino]-methyl}-benza- mide ¹H NMR:(Acetone-d₆)δ(ppm): 9.09(bs, 1H), 8.03(d, J=7.9Hz, 2H), 7.96(d, J=7.5Hz,1H), 7.65(d, J=7.9Hz, 2H), 7.61(d, J=3.5Hz, 1H), 7.51(bs, 2H), 7.41(d,J=8.8Hz, 1H), 7.36(s, 1H), 6.95(d, J=6.2Hz, 1H), 6.35(d, J=3.5Hz, 1H),4.85(s, 2H), 4.20(t, J=5.7Hz, 2H), 3.69)t, J=4.4Hz, 4H), 2.87-2.81(m,2H), 2.62-2.57 (m, 4H). 33, 60 429 574

N-(4-Amino-thiophen-3-yl)-4-[(3,4,5-tri- methoxy-phenyl-amino)-methyl]-benzamide ¹H NMR(DMSO-d₆): δ9.66(brs, 1H), 7.94(d,J=7.5Hz, 2H), 7.56(d, J=7.9Hz, 2H), 6.22-6.16(m, 1H), 5.94(s, 2H),4.91(s, 2H), 4.38(d, J=5.7Hz, 4H), 3.70 (s, 6H), 3.55(s, 3H). 33, 60 430575

N-(4-Amino-thiophen-3-yl)-4-(5-meth- oxy-1H-benzo-imidazol-2-ylsulfanyl- methyl)-benzamide (DMSO)δ(ppm): 12.43(bs, 1H),9.59(bs, 1H), 7.84(d, J=8.1Hz, 2H), 7.56(d, J=8.1Hz, 2H), 7.48(d,J=3.7Hz, 1H), 7.32(bs, 1H, SCH), 6.96(bs, 1H, SCH), 6.74(dd, J=8.8,2.2Hz, 1H), 6.11(d, J=3.7Hz, 1H), 4.84(s, 2H), 4.59(s, 2H), 3.76(s, 3H).LRMS: 410.1(calc)(M); 411.2(found)(M + H)+ 36, 60 431 576

2-{4-(4-Methoxy-benzyl- amino)-phenyl]-cyclo- propanecarboxylicacid(2-amino-phenyl)-amide ¹H-NMR(DMSO-d6), δ(ppm): 9.22(bs, 1H),8.19(bs, 1H), 7.63(d, J=7.1Hz, 1H), 7.53(t, J=4.2Hz, 1H), 7.41 (dd,J=9.2, 1.5Hz, 1H), 7.25(d, J=8.3Hz, 2H), 7.06(d, J=7.1Hz, 1H), 6.85(d,J=8.3Hz, 2H), 6.62-6.59(m, 3H), 4.51(d, J=4.2Hz, 2H), 3.78(s, 3H),2.77(d, J=3.1Hz, 1H), 2.45(d, J=1.1Hz, 1H), 1.22(m, 1H), 1.05(m, 1H).432 577

N-(2-Amino-phenyl)-4-(3-cya- no-6-methyl-pyridin-2-yloxy-methyl)-benzamide ¹H NMR(DMSO-d₆)δ(ppm): 9.72(brs, 1H), 8.23(d, J=7.5Hz,1H), 8.06(d, J=7.9Hz, 2H), 7.67(d, J=7.9Hz, 2H), 7.23(d, J=7.9Hz, 1H),7.15(d, J=7.9Hz, 1H), 7.03(t, J=7.5Hz, 1H), 6.84(d, J=7.9Hz, 1H),6.65(t, J=7.5hz, 1H), 5.62(brs, 2H), 4.97(brs, 2H) 11 433 578

N-(2-Amino-phenyl)-4-{[4-(6-meth- oxy-pyridin-3-yl)-py-rimidin-2-ylamino]-meth- yl}-benzamide ¹H NMR(300MHz, DMSO-D₆)δ(ppm):9.63(s, 1H), 8.95(d, J=2.2Hz, 1H), 8.40(d, J=5.3Hz, 2H), 7.96 (m, 3H),7.54(d, J=7.5Hz, 2H), 7.22(dd, J=5.3, 7.8Hz, 2H), 7.01(m, 2H), 6.83(d,J=7.5Hz, 1H), 6.64 (dd, J=7.0, 7.9Hz, 1H), 4.92(s, 2H), 4.70(d, J=6.2Hz,2H), 3.98(s, 3H). 15, 33 434 579

2-Acetyl- amino-5-[4-(2-amino- phenylcarba- moyl)-benzyl]-thiophene-3-car- boxamide ¹H NMR: (DMSO)δ(ppm): 11.98(bs, 1H),9.61(bs, 1H), 7.93(d, J=8.1Hz, 2H), 7.81(s, 1H), 7.45(s, 1H), 7.38(d,J=8.1Hz, 1H), 7.19(s, 1H), 7.16(d, J=7.3Hz, 1H), 6.97(dd, J=7.0, 7.0Hz,1H), 6.77(d, J=7.3Hz, 1H), 6.59(dd, J=7.3, 7.3Hz, 1H), 4.88(bs, 2H),4.10(s, 2H), 2.15(s, 3H). 49 435 580

N-(2-Amino-phenyl)-4-[(3-meth- yl-2-methyl- amino-3H-benzo-imidazol-3H-benzo- imidazol-5-ylamino)-meth- yl]-benzamide ¹HNMR(DMSO)δ(ppm): 9.56(s, 1H), 7.90(d, J=7.9Hz, 2H), 7.49(d, J=7.9Hz,2H), 7.15(d, J=7.5Hz, 1H), 6.95(t, J=7.5Hz, 1H), 6.78(dd, J=13.2,8.35Hz, 2H), 6.58(t, J=7.5Hz, 1H), 6.39(s, 1H), 6.31 (m, 2H), 5.75(t,J=6.15Hz, 1H), 4.87(s, 2H), 4.32(d, J=5.7Hz, 2H), 3.34(s, 3H), 2.82(d,J=8.5Hz, 3H). 61 438 591

5-(5-Methoxy-1H-benzo- imidazol-2-ylsulfanyl- methyl)-benzo-furan-2-carboxylic acid(2-a- mino-phenyl)amide ¹H NMR(DMSO)δ(ppm):9.84(s, 1H), 7.84(s, 1H), 7.67(s, 1H), 7.63(d, J=8.5Hz, 1H), 7.55(d,J=9.0Hz, 1H), 7.17(d, J=8.0Hz, 1H), 6.97(t, J=7.5Hz, 1H), 6.78(d,J=8.0Hz, 1H), 6.78-6.74(m, 3H), 6.59(t, J=7.5Hz, 1H), 5.71(s, 2H),4.94(s, 1H), 4.65(s, 2H), 3.76(s, 3H). 64 439 592

5-(3,4,5-Trimethoxy-benzyl- amino)-benzo- furan-2-carboxylicacid(2-amino-phenyl)-amide ¹H NMR(DMSO)δ(ppm): 9.69(s, 1H), 7.47(s, 1H),7.41(d, J=8.8Hz, 1H), 7.19(d, J=6.6Hz, 1H), 6.97 (dd, J=7.5, 7.5Hz, 1H),6.89(dd, J=8.8, 2.2Hz, 1H), 6.79-6.78(m, 2H), 6.74(s, 2H), 6.60(dd,J=7.5, 7.5Hz, 1H), 6.14(t, J=5.7Hz, 1H), 4.92(s, 2H), 4.21(d, J=5.7Hz,1H), 3.75(s, 6H), 3.31(s, 3H). 64

Example 122

Step 1: {2-[(3′-Formyl-biphenyl-4-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester (185)

Following the procedure described in Example 15, step 1, butsubstituting 184 for 140, the title compound 185 was obtained in 74%yield. ¹H NMR (CDCl₃): δ 10.10 (s, 1H), 9.41(s, 1H), 8.13 (m, 1H), 8.07(d, J=8.4 Hz, 2H), 7.89 (m, 2H), 7.77 (m, 1H), 7.70 (d, J=8.4 Hz, 2H),7.64 (m, 1H), 7.27-7.09 (m, 3H), 7.03 (s, 1H), 1.52 (s, 9H).

Step 2: N-(2-Aminophenyl)-4-[3-(indan-2-ylaminomethyl)phenyl)]-benzamide(186)

To a stirred solution of biphenyl aldehyde (104 mg, 0.25 mmol) and2-aminoindane (33.3 mg, 0.25 mmol) in dichloroethane (1 mL) was addedsodium triacetoxyborohydride (80 mg, 0.375 mmol) followed by a glacialacetic acid (15 ul, 0.25 mmol), and then the mixture was stirred at roomtemperature for 3 h. After a removal of the volatiles, the residue waspartitioned between ethyl acetate and 10% aqueous sodium bicarbonatesolution. The combined organic layers were washed with water, dried andconcentrated. Purification by flash chromatography (10% methanol inchloroform) gave the desired Boc-monoprotected product (112 mg, 84%yield) as a white solid. ¹H NMR (CDCl₃):

9.21 (s, 1H), 8.03 (d, J=8.7 Hz, 2H), 7.83 (m, 1H), 7.69 (d, J=8.7 Hz,2H), 7.65 (s, 1H), 7.54-7.38 (m, 3H), 7.28 (m, 7H), 6.82 (s, 1H), 3.95(s, 2H), 3.74 (m, 1H), 3.22 (dd, J=15.6, 6.9 Hz, 2H), 2.89 (dd, J=15.6,6.6 Hz, 2H), 1.53 (s, 9H).

Following the procedure described in Example 42, step 3, butsubstituting the previous compound for 46, the title compound 186 wasobtained in 98% yield. ¹H NMR (20% CD₃OD in CDCl₃): δ 7.95 (d, J=8.4 Hz,2H), 7.65 (d, J=8.4 Hz, 2H), 7.57 (m, 1H), 7.54-6.79 (m, 11H), 3.95 (s,2H), 3.66 (m, 1H), 3.16 (dd, J=15.6, 6.9 Hz, 2H), 2.81 (dd, J=15.6, 6.6Hz, 2H).

Examples 123-126

Examples 123 to 126 (compounds 187-190) were prepared using the sameprocedure as described for compound 186 in Example 122 (scheme 21).

Example 127

Step 1: {2-[4-(1-Amino-cyclohexylethynyl)-benzoylamino]-phenyl}-carbamicacid tert-butyl ester (191)

A mixture of iodide 184 (438 mg, 1.0 mmol), Pd(PPh₃)₂Cl₂ (35 mg, 0.05mmol), triphenylphosphine (7.6 mg, 0.025 mmol), and1-ethynylcyclohexylamine (185 mg, 1.5 mmol) was stirred at roomtemperature in THF (4 mL) containing triethylamine (0.56 mL, 4.0 mmol)for 20 min. To this Cul (3.8 mg, 0.02 mmol) was added and stirringcontinued for 2 h. The reaction mixture was then diluted with ethylacetate (30 mL), washed with water, and the organic layer was dried andconcentrated. Purification by flash chromatography (10% methanol inchloroform) gave the desired product 191 (420 mg, 97% yield). ¹H NMR(CDCl₃): δ 9.36 (s, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.77 (d, J=7.5 Hz, 1H),7.47 (d, J=8.4 Hz, 2H), 7.25-6.85 (m, 3H), 2.10-1.30 (m. 10H), 1.51 (s,9H).

Step 2:N-(2-Aminophenyl)-4-[1-(4-methoxy-benzylamino)-cyclohexylethynyl]-benzamide(192)

Following the procedure described in Example 122, step 2, butsubstituting p-anisaldehyde for 2-aminoindane, the title compound 192was obtained in 74% yield. ¹H NMR (CDCl₃): δ 8.44 (s, 1H), 7.82 (d,J=8.1 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.23 (m,1H), 7.05 (m,1H), 6.84 (d, J=8.7 Hz, 2H), 6.78 (m, 2H), 3.97 (s, 2H),3.76 (s, 3H), 2.10-1.30 (m, 10H).

Example 133

Step 1:N-[2-(t-Butyloxycarbonyl)-amino-phenyl]-4-(trimethylsilylethynyl)benzamide(197)

To a stirred solution of 184 (5.00 g, 11.41 mmol) in anhydrous THF (100ml) under nitrogen at 0° C. were added Pd(PPh₃)₂Cl₂ (240 mg, 0.34 mmol),Cul (130 mg, 0.69 mmol), and trimethylsilylacetylene (2.10 ml, 14.84mmol), respectively. Then, anhydrous Et₃N (6.36 ml, 45.66 mmol) wasadded dropwise. The temperature was slowly warmed up to room temperatureover 4 h. The reaction mixture was poured into a saturated aqueoussolution of NH₄Cl, and diluted with ethyl acetate. After separation, theorganic layer was successively washed with sat. NH₄Cl, H₂O and brine,dried over anhydrous MgSO₄, filtered and concentrated. The crude residuewas then purified by flash chromatography on silica gel (AcOEt/hexane:20/80→50/50) to afford the title compound 197 (4.42 g, 10.83 mmol, 94%yield) as a yellow powder. ¹H NMR (300 MHz, CDCl₃) δ (ppm): 9.26 (bs,1H), AB system (δ_(A)=7.91, δ_(B)=7.55, J=8.3 Hz, 4H), 7.85 (d, J=7.9Hz, 1H), 7.32-7.13 (m, 3H), 6.70 (bs, 1H), 1.53 (s, 9H), 0.28 (s, 9H).

Step 2: N-(2-Amino-phenyl)-4(trimethylsilylethynyl)benzamide (198)

Following the procedure described in Example 42, step 3, butsubstituting the previous compound for 46, the title compound 198 (70mg, 0.23 mmol) was obtained as a white solid with a major fractioncomposed of a mixture of 198 and 199. ¹H NMR (300 MHz, acetone-d₆) δ(ppm): 9.20 (bs, 1H), AB system (δ_(A)=8.07, δ_(B)=7.62, J=8.2 Hz, 4H),7.32 (d, J=7.6 Hz, 1H), 7.05 (td, J=7.6, 1.2 Hz, 1H), 6.90 (d, J=7.6 Hz,1H), 6.72 (t, J=7.3 Hz, 1H), 4.66 (bs, 2H), 0.30 (s, 9H).

Step 3: N-(2-Amino-phenyl)-4-ethynylbenzamide (199)

To a stirred solution at −20° C. of a mixture of 198 and 199 inanhydrous THF (15 ml) under nitrogen was added a solution of TBAF (1 ml,1.0 M in THF). The reaction mixture was allowed to warm up to roomtemperature over 2 h and stirred at room temperature for 18 h. Then, thereaction mixture was poured into a saturated aqueous solution of NH₄Cland diluted with ethyl acetate. After separation, the organic layer wassuccessively washed with sat. NH₄Cl, H₂O and brine, dried over anhydrousMgSO₄, filtered and concentrated. The crude residue was then purified byflash chromatography on silica gel (AcOEt/hexane: 30/70) to afford thetitle compound 199 (215 mg, 0.91 mmol, 46% yield over 2 steps) as a paleyellow powder. ¹H NMR (300 MHz, acetone-d₆) δ (ppm): 9.19 (bs, 1H), ABsystem (δ_(A)=8.08, δ_(B)=7.66, J=8.5 Hz, 4H), 7.33 (d, J=7.6 Hz, 1H),7.05 (t, J=7.3 Hz, 1H), 6.91 (d, J=7.6 Hz, 1H), 6.72 (t, J=7.6 Hz, 1H),4.67 (bs, 2H), 3.88 (s, 1H).

Example 134

Step 1: N-[2(t-Butyloxycarbonyl)-amino-phenyl]-4-ethynylbenzamide (200)

To a stirred solution at −20° C. of a mixture of 199 (3.48 g, 8.53 mmol)in anhydrous THF (50 ml) under nitrogen was slowly added a solution ofTBAF (9.4 ml, 9.38 mmol, 1.0 M in THF). The reaction mixture was allowedto warm up to room temperature over 2 h and stirred at room temperaturefor 4 h. Then, the reaction mixture was concentrated, diluted with ethylacetate, and successively washed with a saturated aqueous solution ofNH₄Cl, H₂O and brine, dried over anhydrous MgSO₄, filtered andconcentrated. The crude residue was then purified by flashchromatography on silica gel (AcOEt/hexane: 25/75→30/70) to afford thetitle compound 200 (2.53 g, 7.53 mmol, 88% yield) as a pale yellow foam.¹H NMR (300 MHz, CDCl₃) δ (ppm): 9.31 (bs, 1H), AB system (δ_(A)=7.94,δ_(B)=7.59, J=8.5 Hz, 4H), 7.83 (d, J=7.6 Hz, 1H), 7.30-7.10 (m, 3H),6.75 (bs, 1H), 3.23 (s, 1H), 1.53 (s, 9H).

Step 2:N-(2-amino-phenyl)-4-[3-(4-chlorophenyl)-3-morpholin-4-yl-1-propyn-1-yl]-benzamide(201)

To a stirred solution at room temperature of 200 (200 mg, 0.60 mmol) inanhydrous 1,4-dioxane (5 ml) under nitrogen were added4-chlorobenzaldehyde (100 mg, 0.71 mmol), morpholine (60 μl, 0.68 mmol),and Cul (6 mg, 0.03 mmol), respectively. The reaction mixture wasbubbled with nitrogen for 5 min and warmed up to 105° C. After 18 h, thereaction mixture was allowed to cool to room temperature, diluted withethyl acetate, and successively washed with a saturated aqueous solutionof NH₄Cl, H₂O and brine, dried over anhydrous MgSO₄, filtered andconcentrated. The crude residue was then purified by flashchromatography on silica gel (AcOEt/hexane: 40/60) to afford the desiredcompound (193 mg, 0.35 mmol, 59% yield) as a pale yellow foam. ¹H NMR(300 MHz, CDCl₃) δ (ppm): 9.40 (bs, 1H), AB system (δ_(A)=7.96,δ_(B)=7.36, J=8.5 Hz, 4H), 7.79 (d, J=7.9 Hz, 1H), 7.59 (d, J=8.4 Hz,4H), 7.25-7.10 (m, 3H), 6.91 (s, 1H), 4.80 (s, 1H), 3.82-3.68 (m, 4H),2.69-2.58 (m, 4H), 1.53 (s, 9H).

Following the procedure described in Example 42, step 3, butsubstituting the previous compound for 46, the title compound 201 wasobtained in 67% yield. ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.80 (bs, 1H),AB system (δ_(A)=8.06, δ_(B)=7.71, J=8.1 Hz, 4H), AB system (δ_(A)=7.65,δ_(B)=7.52, J=8.3 Hz, 4H), 7.20 (d, J=7.9 Hz, 1H), 7.02 (t, J=7.3 Hz,1H), 6.82 (d, J=7.0 Hz, 1H), 6.64 (t, J=7.5 Hz, 1H), 5.10 (s, 1H), 4.97(bs, 2H), 3.72-3.58 (m, 4H), 2.67-2.46 (m, 4H).

Example 135

Step 1: Methyl4-(4-chloro-6-(2-indanyl-amino)-[1,3,5]triazin-2-yl-amino)-benzoic ester(203)

To a stirred solution at room temperature of 202 (2.00 g, 7.11 mmol) inanhydrous THF (50 ml) under nitrogen were added i-Pr₂NEt (1.86 ml, 10.66mmol) and methyl 4-aminobenzoate (1.29 g, 8.53 mmol) or ArNH₂ (1.2equiv), respectively. The reaction mixture was then refluxed for 24 h.After cooling, the reaction mixture was poured into a saturated aqueoussolution of NH₄Cl, and diluted with AcOEt. After separation, the organiclayer was successively washed with sat. NH₄Cl, H₂O and brine, dried overanhydrous MgSO₄, filtered and concentrated. The crude residue was thenpurified by flash chromatography on silica gel (AcOEt/CH₂Cl₂: 2/98→5/95)to afford the title compound 203 (1.70 g, 4.30 mmol, 60% yield) as abeige powder. ¹H NMR (300 MHz, CDCl₃) δ (ppm): mixture of rotamers, 2 ABsystem (δ_(A)=8.03, δ_(A′)=8.00, δ_(B)=7.70, δ_(B′)=7.61,J_(AB)=J_(A′B′)=8.8 Hz, 4H), 7.43 and 7.31 (2 bs, 1H), 7.29-7.19 (m,4H), 5.84 and 5.78 (2 d, J=7.2 and 7.7 Hz, 1H), 4.98-4.77 (2 m, 1H),3.91 and 3.90 (2 s, 3H), 3.41 (dd, J=16.1, 7.0 Hz, 2H), 2.94 and 2.89 (2dd, J=15.9, 4.9 Hz, 2H).

Step 2:4-[4-amino-6-(2-indanyl-amino)-[1,3,5]-triazin-2-ylamino]-N-(2-amino-phenyl)-benzamide(204)

The title compound 204 was obtained from 203 in 3 steps following thesame procedure as Example 1, Pathway B steps 3-5. ¹H NMR (300 MHz,acetone-d₆) δ (ppm): mixture of rotamers, 8.98 (m,1H), 8.49 and 8.28(2m, 1H), 8.10-7.92 (m, 4H), 7.35-7.14 (m, 5H), 7.03 (td, J=7.6, 1.5 Hz,1H), 6.90 (dd, J=6.6, 1.3 Hz, 1H), 6.71 (td, J=7.6, 1.3 Hz, 1H), 6.57and 6.42 (2m, 1H), 6.04 and 5.86 (2m, 2H), 4.92-4.76 (m, 1H), 4.70-4.58(m, 1H), 3.44-3.26 (m, 2H), 3.08-2.92 (m, 2H). HRMS (calc.): 452.2073,(found): 452.2062.

Example 136

Step 1: Methyl4-[(4-chloro-6-(2-indanyl-amino)-[1,3,5]triazin-2-yloxy)-methyl]-benzoicester (206)

To a stirred solution at 0° C. of 205 (2.00 g, 7.11 mmol) in anhydrousTHF (50 ml) under nitrogen were added i-Pr₂NEt (1.86 ml, 10.66 mmol) andmethyl 4-(hydroxymethyl)benzoate (1.30 g, 7.82 mmol). After few minutes,NaH (95%, 186 mg, 7.11 mmol) was added portionwise. Then, the reactionmixture was allowed to warm to room temperature. After 24 h, thereaction mixture was poured into a saturated aqueous solution of NH₄Cl,and diluted with AcOEt. After separation, the organic layer wassuccessively washed with sat. NH₄Cl, H₂O and brine, dried over anhydrousMgSO₄, filtered and concentrated. The crude residue was then purified byflash chromatography on silica gel (AcOEt/CH₂Cl₂: 2/98) to afford thetitle compound 206 (2.00 g, 4.88 mmol, 69% yield) as a colorless stickyfoam. ¹H NMR (300 MHz, CDCl₃) δ (ppm): mixture of rotamers, 2 AB system(δ_(A)=8.06, δ_(A′)=8.03, δ_(B)=7.52, δ_(B′)=7.46, J_(AB)=J_(A′B′)=8.5Hz, 4H), 7.26-7.17 (m, 4H), 5.94 and 5.85 (2 bd, J=7.8 Hz, 1H), 5.48 and5.39 (2 s, 2H), 4.92-4.76 (2 m, 1H), 3.94 and 3.92 (2 s, 3H), 3.39 and3.33 (2 dd, J=16.0, 7.0 Hz, 2H), 2.89 and 2.84 (2 dd, J=16.0, 4.9 Hz,2H).

Step 2:4-{[4-amino-6-(2-indanyl-amino)-[1,3,5]-triazin-2-yloxy]-methyl}-N-(2-amino-phenyl)-benzamide(207)

The title compound 207 was obtained from 206 in 3 steps following thesame procedure as Example 1, Pathway B steps 3-5. ¹H NMR (300 MHz,acetone-d₆+

DMSO-d₆) δ (ppm): 9.49 (m, 1H), 8.12-8.03 (m, 2H), 7.60 (t, J=7.7 Hz,2H), 7.35 (d, J=7.1 Hz, 1H), 7.28-7.13 (m, 4H), 7.07-6.94 (m, 2H), 6.90(dd, J=7.3, 1.4 Hz, 1H), 6.70 (td, J=7.3, 1.1 Hz, 1H), 6.44 (bs, 1H),6.25 (bs, 1H), 5.47 and 5.41 (2s, 2H), 4.87-4.68 (m, 3H), 3.35-3.20 (m,2H), 3.02-2.88 (m, 2H). HRMS (calc.): 467.2070, (found): 467.2063.

Example 210 Methyl4-[(4-chloro-6-phenethyl-amino-[1,3,5]triazin-2-yl-amino)-methyl]-benzoicester (208)

The title compound 208 was obtained from 2 following the same procedureas in Example 1, pathway B steps 2 (R¹R²NH=phenethylamine).

Step 1: Methyl4-[(4-phenethylamino-[1,3,5]triazin-2-yl-amino)-methyl]-benzoic ester(209)

To a degazed solution of 208 (300 mg, 0.75 mmol) in MeOH (35 mL) wasadded 10% Pd/C (24 mg, 0.023 mmol). The reaction mixture was stirredunder a 1 atm pressure of H₂ at room temperature for 20 h then it waspurged with N₂. The palladium was removed by filtration through celiteand the reaction mixture was concentrated. The crude residue waspurified by flash chromatography on silica gel (MeOH/CH₂Cl₂: 4/96) toafford the title compound 209 (135 mg, 0.37 mmol, 50% yield). ¹H NMR(300 MHz, CDCl₃) δ (ppm): 8.08 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz,2H), 7.50-7.15 (m, 6H), 4.85-4.65 (m, 2H), 3.98 (s, 3H), 3.82-3.62 (m,2H), 3.05-2.85 (m, 2H).

Step 2:N-(2-Amino-phenyl)-4-[(4-phenethylamino-[1,3,5]triazin-2-yl-amino)-methyl]-benzamide(210)

The title compound 210 was obtained from 209 in 2 steps following thesame procedure as in Example 1, steps 4 and 5. ¹H NMR: (300 MHz,acetone-d₆) δ (ppm): 9.03 (s, 1H), 8.17-7.87 (m, 3H), 7.49 (dd, J=19.2,8.2 Hz, 2H), 7.32-7.03 (m, 6H), 6.99 (t, J=7.6 Hz, 1H), 6.86 (d, J=8.0Hz, 1H), 6.67 (t, J=7.4 Hz, 1H), 6.60-6.30 (m, 2H), 4.72 (t, J=6.3 Hz,1H), 4.65-4.56 (m, 1H), 3.67-3.51 (m, 2H), 2.95-2.80 (m, 2H).

Example 138

Step 1: Methyl4-[(4,6-dimethoxy-[1,3,5]triazin-2-yl-amino)-methyl]-benzoic ester (211)

In a 75 ml sealed flask, a stirred suspension of2-chloro-4,6-dimethoxy-1,3,5-triazine (540 mg, 3.08 mmol), methyl4-(aminomethyl)benzoate.HCl 2 (689 mg, 3.42 mmol), i-Pr₂NEt (1.49 ml,8.54 mmol) in anhydrous THF (30 ml) was warmed at 80° C. for 5 h. Then,the reaction mixture was allowed to cool to room temperature, pouredinto a saturated aqueous solution of NH₄Cl, and diluted with AcOEt.After separation, the organic layer was successively washed with sat.NH₄Cl, H₂O and brine, dried over anhydrous MgSO₄, filtered andconcentrated. The crude residue was then purified by flashchromatography on silica gel (AcOEt/CH₂Cl₂: 10/90→30/70) to afford thetitle compound 211 (870 mg, 2.86 mmol, 93% yield) as a white solid. ¹HNMR (300 MHz, CDCl₃) δ (ppm): AB system (δ_(A)=8.01, δ_(B)=7.39,J_(AB)=8.5 Hz, 4H), 6.08-6.00 (m, 1H), 4.73 (d, J=6.3 Hz, 2H), 3.95 (s,6H), 3.92 (s, 3H).

The title compound 212 was obtained from 211 in 2 steps following thesame procedure as Example 1, steps 4 and 5. ¹H NMR (300 MHz,acetone-d₆+ΣDMSO-d₆) δ (ppm): 9.58 (bs, 1H), 8.27 (t, J=6.3 Hz, 1H), ABsystem (δ_(A)=8.04, δ_(B)=7.53, J_(AB)=8.4 Hz, 4H), 7.31 (d, J=6.9 Hz,1H), ), 7.02 (td, J=7.6, 1.6 Hz, 1H), 6.88 (dd, J=7.9, 1.4 Hz, 1H), 6.68(td, J=7.6, 1.4 Hz, 1H), 4.86-4.78 (m, 2H), 4.69 (d, J=6.3 Hz, 2H), ),3.90 and 3.89 (2s, 6H). HRMS (calc.): 380.1597, (found): 380.1601.

Step 2:N-(2-Amino-phenyl)-4-[(4,6-dimethoxy-[1,3,5]-triazin-2-yl-amino)-methyl]-benzamide(212)

Example 139

Step 1:4-[(6-(2-Indanyl-amino)-4-methoxy-[1,3,5]triazin-2-yl-amino)-methyl]-benzoicacid (213)

To a stirred solution at room temperature of 5 (300 mg, 0.73 mmol) in amixture of MeOH/THF (10 ml/5 ml) was added an aqueous solution of KOH(10%, 5 ml). After 3 days, the reaction mixture was concentrated on therotavap, diluted in water and acidified with 1N HCl until pH 5-6 inorder to get a white precipitate. After 15 min, the suspension wasfiltered off and the cake was abundantly washed with water, and dried toafford the title compound 213 (282 mg, 0.72 mmol, 98% yield) as a whitesolid. MS: m/z=392.1 [MH]⁺.

Step 2:N-(2-amino-phenyl)-4-{[6-(2-indanyl-amino)-4-methoxy-[1,3,5]-triazin-2-yl-amino]-methyl}-benzamide(214)

The title compound 214 was obtained from 213 in one step following thesame procedure as Example 1, step 5. ¹H NMR (300 MHz, acetone-d₆+

DMSO-d₆) δ (ppm): mixture of rotamers, 9.69-9.53 (m, 1H), AB system(δ_(A)=8.04, δ_(B)=7.52, J_(AB)=7.8 Hz, 4H), 7.80-7.60 (m, 1H),7.45-7.10 (m, 6H), 7.01 (t, J=7.6 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 6.68(t, J=7.6 Hz, 1H), 4.92-4.60 (m, 5H), 3.90-3.78 (m, 3H), 3.35-3.22 (m,2H), 3.02-2.83 (m, 2H). HRMS (calc.): 481.2226, (found): 481.2231.

Example 29

Step 1: Methyl4-[(4,6-dichloro-[1,3,5]triazin-2-yl-N-methyl-amino)-methyl]-benzoicester (216)

To a stirred suspension at room temperature of NaH (95%, 81 mg, 3.19mmol) in anhydrous THF (10 ml) under nitrogen were successively added asolution of 3 (500 mg, 1.60 mmol) in anhydrous THF (10 ml) and Mel (298μl, 4.79 mmol). After 16 h, the reaction mixture was poured into asaturated aqueous solution of NH₄Cl, and diluted with AcOEt. Afterseparation, the organic layer was successively washed with sat. NH₄Cl,H₂O and brine, dried over anhydrous MgSO₄, filtered and concentrated.The crude residue was then purified by flash chromatography on silicagel (AcOEt/hexane: 10/90→20/80) to afford the title compound 215 (200mg, 0.61 mmol, 38% yield) as a white crystalline solid. ¹H NMR (300 MHz,CDCl₃) δ (ppm): AB system (δ_(A)=8.04, δ_(B)=7.31, J_(AB)=8.2 Hz, 4H),4.93 (s, 2H), 3.93 (s, 3H), 3.18 (s, 3H).

Step 2:4-{[4-amino-6-(2-indanyl-amino)-[1,3,5]-triazin-2-yl-N-methyl-amino]-methyl}-N-(2-amino-phenyl)-benzamide(216)

The title compound 216 from 215 in 4 steps was obtained following thesame procedure as Example 1, Pathway B steps 2-5. ¹H NMR (300 MHz,acetone-d₆) δ (ppm): 9.11 (bs, 1H), 8.03 (d, J=8.0 Hz, 2H), 7.43 (bs,2H), 7.33 (d, J=7.7 Hz, 1H), ), 7.28-7.09 (m, 4H), 7.04 (td, J=7.6, 1.5Hz, 1H), 6.90 (dd, J=8.0, 1.4 Hz, 1H), 6.71 (td, J=7.5, 1.3 Hz, 1H),6.25-6.05 (m, 1H), 5.82 and 5.64 (2bs, 2H), 5.00-4.56 (m, 5H), 3.42-2.76(m, 7H). HRMS (calc.): 480.2386. (found): 480.2377.

Example 141

Step 1: Methyl4-[(4-chloro-6-methyl-[1,3,5]triazin-2-yl-amino)-methyl]-benzoic ester(217)

To a stirred solution at −30° C. of cyanuric chloride 1 (2.00 g, 10.85mmol) in anhydrous THF (100 ml) under nitrogen was slowly added asolution of MeMgBr (17 ml, 23.86 mmol, 1.4 M in anhydrous THF/toluene).After 1 h, the reaction mixture was allowed to warm to room temperatureover 3 h. Then, methyl 4-(aminomethyl)benzoate.HCl 2 (2.08 g, 10.30mmol) and i-Pr₂NEt (3.78 ml, 21.69 mmol) were added, respectively. After18 h, the reaction mixture was poured into a saturated aqueous solutionof NH₄Cl, and diluted with AcOEt. After separation, the organic layerwas successively washed with sat. NH₄Cl, H₂O and brine, dried overanhydrous MgSO₄, filtered and concentrated. The crude residue was thenpurified by flash chromatography on silica gel (AcOEt/CH₂Cl₂:10/90→15/85) to afford the title compound 217 (780 mg, 2.67 mmol, 25%yield) as a yellow powder. ¹H NMR (300 MHz, CDCl₃) δ (ppm): mixture ofrotamers, 2 AB system (δ_(A)=8.03, δ_(A′)=8.02, δ_(B)=7.39, δ_(B′)=7.38,J=8.5 Hz, 4H), 6.28-6.08 (2 m, 1H), 4.76 and 4.74 (2d, J=6.3 Hz, 2H),3.92 (s, 3H), 2.46 and 2.42 (2s, 3H).

Step 2:N-(2-amino-phenyl)-4-{[6-(2-indanyl-amino)-4-methyl-[1,3,5]-triazin-2-yl-amino]-methyl}-benzamide(218)

The title compound 218 was obtained from 217 in 3 steps following thesame procedure as Example 1, steps 3-5. ¹H NMR (300 MHz,acetone-d₆+ΣDMSO-d₆) δ (ppm): mixture of rotamers, 9.62-9.50 (m, 1H),8.04 (d, J=8.0 Hz, 2H), 7.68-7.37 (m, 3H), 7.33 (d, J=7.7 Hz, 1H),7.28-7.07 (m, 5H), 7.02 (t, J=7.4 Hz, 1H), 6.89 (d, J=7.9 Hz, 1H), 6.69(t, J=7.4 Hz, 1H), 4.92-4.60 (m, 5H), 3.35-3.10 (m, 2H), 3.02-2.82 (m,2H), 2.25-2.12 (m, 3H).

Example 142

Step 1:(2-{4-[2-(4,6-Diamino-[1,3,5]triazin-2-yl)-vinyl]-benzoylamino}-phenyl)-carbamictert-butyl ester (219)

To a degazed solution of 184 (40 mg, 0.091 mmol) and2-vinyl-4,6-diamino-1,3,5-triazine (11 mg, 0.083 mmol) in dry DMF (1 mL)was added tri-o-tolylphosphine (POT) (1.5 mg, 0.005 mmol) followed byEt₃N (46 μL, 0.33 mmol) and tris(dibenzylideneacetone)dipalladium(0) (2mg, 0.0025 mmol). The solution was heated at 100° C. for 16h. Then, DMFwas removed under reduced pressure. The reaction mixture was partitionedbetween AcOEt and a solution of sat. NH₄Cl. After separation, theorganic layer was washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated. The crude residue was then purified by flashchromatography on silica gel (MeOH/CH₂Cl₂: 5/95) to afford the titlecompound 219 (25 mg, 0.056 mmol, 67% yield). ¹H NMR (300 MHz,Acetone-d₆) δ (ppm): 8.27 (s, 1H), 8.06 (d, J=8.1 Hz, 2H), 7.96 (d,J=15.9 Hz, 1H), 7.79 (d, J=8.1 Hz, 2H), 7.76-7.69 (m, 1H), 7.62-7.55 (m,1H), 7.26-7.15 (m, 2H), 6.90 (d, J=15.9 Hz), 6.21 (s, 4H), 1.50 (s, 9H).

Step 2:N-(2-Amino-phenyl)-4-[2-(4,6-diamino-[1,3,5]triazin-2-yl)-vinyl]-benzamide(220)

To a stirred solution at room temperature of 219 (25 mg, 0.056 mmol) inCH₂Cl₂ (1.5 mL) was added TFA (0.3 mL, 4.3 mmol). After 30 min, asolution of sat. NaHCO₃ was slowly added until pH 8 is reached, CH₂Cl₂was removed under reduced pressure, AcOEt was added, and the phases wereseparated. The organic layer was washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated. The crude residue was purified byflash chromatography on silica gel (MeOH/CH₂Cl₂: 10/90) to afford thetitle compound 220 (19 mg, 0.054 mmol, 98% yield). ¹H NMR (300 MHz,acetone-d₆) δ (ppm): 8.33, 8.13 (2d, J=7.5 Hz, 1H), 8.22 (d, J=15.9 Hz,1H), 8.01 (d, J=8.1 Hz, 2H), 7.84 (d, J=8.1 Hz, 2H), 7.38-6.96 (m, 2H),7.03 (d, J=15.9 Hz, 1H), 6.94-6.62 (m, 2H).

Example 143a

Step 1: 2-Amino-4-chloro-6-piperidin-1-yl-[1,3,5]triazin (221)

Ammonia was bubbled for 5 min in a solution of2,4-dichloro-6-piperidin-1-yl-[1,3,5]triazine (500 mg, 2.15 mmol) in dry1,4-dioxane (20 mL). The solution was heated at 70° C. for 16 h in asealed tube. The reaction mixture was allowed to cool to roomtemperature, and partitioned between AcOEt and a solution of sat. NH₄Cl.After separation, the organic layer was washed with water and brine,dried over anhydrous Na₂SO₄, filtered and concentrated to afford thetitle compound 221 (453 mg, 2.12 mmol, 98% yield). LRMS: [MH]⁺=214.1.

Step 2: 2-Amino 4-piperidin-1-yl-6-vinyl-[1,3,5]triazin (222)

To a solution of 221 (358 mg, 1.68 mmol) in dry toluene (7 mL) was addedtributyl(vinyl)tin (514 μL, 1.76 mmol) followed by Pd(PPh₃)₄ (97 mg,0.084 mmol) and the reaction mixture was heated at 100° C. for 16 h in asealed tube. Then, the reaction mixture was allowed to cool to roomtemperature, concentrated, and purified directly by flash chromatographyon silica gel (AcOEt/hexane: 10/90→30/70) to afford the title compound222 (containing tributyltin chloride).

Steps 3:N-(2-Amino-phenyl)-4-[2-(4-amino-6-piperidin-1-yl-[1,3,5]triazin-2-yl)-vinyl]-benzamide223)

The title compound 223 was obtained from 222 in 2 steps following thesame procedure as in scheme 31, steps 1 and 2. ¹H NMR: (300 MHz,DMSO-d₆) δ (ppm): 9.69 (s, 1H), 8.01 (d, J=7.5 Hz, 2H), 7.87 (d, J=16.0Hz, 1H), 7.80 (d, J=7.5 Hz, 2H), 7.18 (d, J=7.5 Hz, 1H), 7.04-6.92 (m,1H), 6.91 (d, J=16 Hz, 1H), 6.85-6.68 (m, 3H), 6.60 (t, J=7.2 Hz, 1H),4.93 (s, 2H), 3.77 (s, 4H), 1.63 (s, 2H), 1.52 (s, 4H).

Example 143b

Step 4:N-(2-Amino-phenyl)-4-[2-(4-amino-6-piperidin-1-yl-[1,3,5]triazin-2-yl)-ethyl]-benzamide(224)

To a solution of 223 (18 mg, 0.043 mmol) in MeOH (5 mL) was added 10%Pd/C (10 mg, 0.021 mmol). The reaction mixture was shaked under apressure of H₂ (40 psi) at room temperature for 16 h using anhydrogenation apparatus. Then, the reaction mixture was purged with N₂,filtered through celite, and concentrated. The crude residue was thenpurified by flash chromatography on silica gel (MeOH/CH₂Cl₂: 2/98→4/96)to afford the title compound 224 (10 mg, 0.024 mmol, 56% yield). ¹H NMR(300 MHz, CDCl₃—CD₃OD) δ (ppm): 7.82 (d, J=8.1 Hz, 2H), 7.35 (d, J=8.1Hz, 2H), 7.08 (t, J=7.0 Hz, 1H), 6.89-6.79 (m, 2H), 7.80-6.90 (m, 1H),3.76 (s, 4H), 3.13 (t, J=8.1 Hz, 2H), 2.88 (t, J=8.1 Hz, 2H),1.90-1.40(m, 10H).

Example 144

Step 1: 2-Amino-benzothiazol-6-ol (225):

A suspension of 2-amino-6-methoxybenzothiazole (5.00 g, 27.8 mmol) indichloromethane (70 mL) was cooled to 0° C. under nitrogen and borontribromide (3.93 mL, 41.6 mmol) was added dropwise. The light yellowmixture was stirred for 3 h, allowing to warm-up slowly from 0° C. to10° C. The reaction was slowly quenched by dropwise addition of methanoland tafter stirring overnight at room temperature, the white solid wascollected by filtration (6.04 g, 88% yield). This hydrobromic salt wasdissolved in water, washed with ethyl acetate, and neutralized with asaturated aqueous solution of NaHCO₃. The resulting crystals werecollected by filtration and dried in the oven at 135° C. for 1 h toafford the title compound 225 as colorless crystals (3.63 g, 79% yield).¹H NMR: (CD₃OD) δ (ppm): 7.27 (d, J=8.8 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H),6.80 (dd, J=8.4, 2.2 Hz, 1H).

Step 2: 6-(2-Morpholin-4-yl-ethoxy)-benzothiazol-2-ylamine (226)

To a solution of benzothiazole 225 (3.62 g, 21.8 mmol) in THF at roomtemperature under nitrogen, were successively added4-(2-hydroxyethyl)morpholine (3.17 mL, 26.1 mmol), triphenylphosphine(7.43 g, 28.3 mmol) followed by a dropwise addition of diethylazodicarboxylate (4.46 mL, 28.3 mmol). The solution was stirred for 3.5h and THF was partially removed in vacuo. The mixture was partitionedbetween ethyl acetate and H₂O. The combined organic layers wereextracted with 1N HCl. The combined acidic extracts were neutralizedusing a saturated aqueous solution of NaHCO₃ and the precipitate wasdissolved with ethyl acetate. These combined organic layers were washedwith brine, dried over MgSO₄, and concentrated. The filtrate wasconcentrated to afford the title compound 226 (5.83 g, 96% yield) as alight yellow oil. ¹H NMR: (Acetone-d₆) δ (ppm): 7.37 (d, J=8.8 Hz, 1H),7.34 (d, J=2.6 Hz, 1H), 6.94 (dd, J=8.8, 2.6 Hz, 1H), 6.60 (bs, 2H),4.19 (t, J=6.2 Hz, 2H), 3.70-3.67 (m, 4H), 2.90 (s, 2H), 2.81 (t, J=6.2Hz, 2H), 2.62-2.58 (m, 4H).

Step 3:4-{[6-(2-Morpholin4-yl-ethoxy)-benzothiazol-2-ylamino]-methyl}-benzoicacid methyl ester (227):

To a round-bottom flask containing benzothiazole 226 (5.80 g, 20.8 mmol)was added methyl 4-formylbenzoate (5.11 g, 31.1 mmol), followed by THF(8 mL), dibutyltin dichloride (315 mg, 1.04 mmol) and dropwise additionof phenylsilane (3.24 mL, 31.1 mmol). The resulting mixture was stirredovernight at room temperature under nitrogen. The mixture was diluted inethyl acetate and filtered. The filtrate was partitioned between ethylacetate and water and the combined organic layers were washed with 1NHCl. The combined acidic layers were neutralized using a saturatedaqueous solution of NaHCO₃ and the precipitate was extracted with ethylaceate. The combined organic layers were washed with brine, dried overMgSO₄, and concentrated. The resulting crude was purified by flashchromatography using MeOH/CHCl₃ (10:90) to afford 227 (3.69 g, 42%yield). ¹H NMR: (Acetone-d₆) δ (ppm): 8.04 (d, J=8.5 Hz, 2H), 7.65 (d,J=8.8 Hz, 2H), 7.41 (d, J=8.8 Hz, 1H), 7.34 (d, J=2.5 Hz, 1H), 6.94 (dd,J=8.5, 2.7 Hz, 1H), 4.50 (t, J=5.5 Hz, 2H), 3.86 (s, 3H).

Step 4:N-(2-Amino-phenyl)-4-{[6-(2-morpholin-4-yl-ethoxy)-benzothiazol-2-ylamino]-methyl}-benzamide(228):

Following the procedure described in Example 1, step 4, 5 butsubstituting the previous compound for 6, the title compound 228 wasobtained (958 mg, 46%) as a colorless solid. ¹H NMR: (CD₃OD) δ (ppm):8.04 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.40 (d, J=8.8 Hz, 1H),7.31 (d, J=2.5 Hz, 1H), 7.25 (d, J=7.4 Hz, 1H), 7.15 (t, J=7.4 Hz, 1H),6.97 (dd, J=8.8, 2.5 Hz, 2H), 6.84 (t, J=7.4 Hz, 1H), 4.78 (s, 2H), 4.21(t, J=5.2 Hz, 2H), 3.81-3.77 (m, 4H), 2.87 (t, J=5.5. 2H), 2.69-3.66 (m,4H).

Example 145

Step 1: 4-[(5-Bromo-benzothiazol-2-ylamino)-methyl]-benzoic acid methylester (229):

Following the procedure described in Example 144, step 3, butsubstituting the 2-amino-6-bromobenzothiazole for 226, the titlecompound 229 was obtained in 56% yield. ¹H NMR: (DMSO-d₆) δ (ppm): 8.78(t, J=5.9 Hz, 1H), 8.01 (d, J=8.2 Hz, 2H), 7.99 (s, 1H), 7.56 (d, J=8.2Hz, 2H), 7.43-7.34 (m, 2H), 4.74 (d, J=5.9 Hz, 2H), 3.90 (s, 3H).

Step 2:4-{[5-(3,4,5-Trimethoxy-phenyl)-benzothiazol-2-ylamino]-methyl}-benzoicacid methyl ester (230):

Following the procedure described in Example 15, step 1, butsubstituting 229 for 140, the title compound 230 was obtained in44%yield as colorless crystals. ¹H NMR: (DMSO-d₆) δ (ppm): 8.73 (t,J=5.7 Hz, 1H), 8.11 (d, J=1.8 Hz, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.63-7.57(m, 3H), 7.48 (d, J=8.4 Hz, 1H), 6.97 (s, 2H), 4.77 (d, J=5.7 Hz, 2H),3.92 (m, 6H), 3.90 (s, 3H), 3.74 (s, 3H).

Step 3:N-(2-Amino-phenyl)-4-{[5-(3,4,5-trimethoxy-phenyl)-benzothiazol-2-ylamino]-methyl}-benzamide(231):

Following the procedure described in Example 1, step 4, 5 butsubstituting the previous compound for 6, the title compound 231 wasobtained in 69% yield. ¹H NMR: (Acetone-d₆) δ (ppm): 8.31 (d, J=7.9 Hz,2H), 8.20 (d, J=7.5 Hz, 1H), 8.13 (s, 1H), 7.73-7.58 (m, 3H), 7.63 (d,J=7.5 Hz, 2H), 7.48-7.43 (m, 2H), 7.05 (s, 2H), 4.98 (s, 2H), 4.00 (s,6H), 3.84 (s, 3H).

Example 146

Step 1: 4-[(6-Methoxy-benzothiazol-2-ylamino)-methyl]-benzoic acidmethyl ester (232):

To a solution of 2-amino-6-methoxybenzothiazole (2.00 g, 11.1 mmol) in amixture of dichloroethane (20 mL) and THF (20 mL), were successivelyadded methyl 4-formylbenzoate (1.82 g, 11.1 mmol), sodiumtriacetoxyborohydride (3.53 g, 16.7 mmol) and acetic acid (1.27 mL, 22.2mmol). The mixture was stirred over 2 days and was quenched by addingaqueous saturated solution of NaHCO₃. The mixture was poured in aseparating funnel containing water and was extracted withdichloromethane. The combined organic extracts were washed with brine,dried over MgSO₄ and concentrated in vacuo. The crude material waspurified by flash chromatography using EtOAc/hexane (20:80 to 30:70) toafford the title compound 232 (1.85 g, 51% yield). ¹H NMR: (Acetone-d₆)δ (ppm): 8.04 (d, J=8.5 Hz, 2H), 7.65 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.8Hz, 1H), 7.34 (d, J=2.5 Hz, 1H), 6.94 (dd, J=8.5, 2.7 Hz, 1H), 4.50 (t,J=5.5 Hz, 2H), 3.86 (s, 3H).

Step 2:N-(2-Amino-phenyl)-4-[(6-methoxy-benzothiazol-2-ylamino)-methyl]-benzamide(233):

Following the procedure described in Example 1, step 4, 5 butsubstituting the previous compound for 6, the title compound 233 wasobtained in 19% yield as a light beige solid. ¹H NMR: (DMSO-d₆) δ (ppm):9.68 (s, 1H), 8.44 (t, J=5.8 Hz, 1H), 8.00 (d, J=8.2 Hz, 2H), 7.55 (d,J=8.2 Hz, 2H), 7.39 (d, J=2.7 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.21 (d,J=6.6 Hz, 1H), 7.05 (t, J=6.3 Hz, 1H), 7.00 (d, J=1.4 Hz, 1H), 6.88 (dd,J=8.8, 2.7 Hz, 1H), 6.86 (dd, J=8.0, 1.4 Hz, 1H), 6.65 (td, J=7.4, 1.4Hz, 1H), 4.95 (s, 2H), 4.70 (d, J=5.8 Hz, 2H), 3.79 (s, 3H).

Example 147

Step 1: 4-(6-Methoxy-1H-benzoimidazol-2-ylsulfanylmethyl)-benzoic acidmethyl ester hydrobromide (234):

To a solution of methyl 4-(bromomethyl)benzoate (2.51 g, 11.0 mmol) inDMF (50 mL) was added 5-methoxy-2-benzimidazolethiol (1.98 g, 11.0mmol). The mixture was stirred at room temperature for 24 h and thesolvent was evaporated in vacuo. The residue was suspended in ethylacetate and the hydrobromide salt was collected by filtration to affordthe title compound 234 (4.10 g, 91% yield) as a colorless solid. ¹H NMR:(DMSO-d₆) δ (ppm): 7.90 (d, J=8.2 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.45(d, J=8.2 Hz, 1H), 7.03 (s,1H), 6.94 (d, J=8.2 Hz,1H), 4.65 (s,2H), 3.82(s,3H), 3.79 (s, 3H).

Step 2:4-[6-(2-Morpholin4-yl-ethoxy)-1H-benzoimidazol-2-ylsulfanylmethyl]-benzoicacid methyl ester (235):

Following the procedure described in Example 144, step 1, 2 butsubstituting the previous compound for 2-amino-6-methoxybenzothiazole,the title compound 235 was obtained in 37% yield. ¹H NMR: (CDCl₃) δ(ppm): 8.04-8.00 (m, 2H), 7.77-7.72 (m, 1H), 7.69-7.59 (m, 1H),7.56-7.49 (m, 2H), 6.96-6.90 (m, 1H), 4.68 (s, 2H), 4.31-4.16 (m, 4H),3.97 (s, 3H), 3.98-3.91 (m, 2H), 3.82-3.72 (m, 2H), 2.75-2.47 (m, 4H).

Step 3:N-(2-Amino-phenyl)-4-[6-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-ylsulfanylmethyl]-benzamide(236):

Following the procedure described in Example 1, step 4, 5 butsubstituting the previous compound for 6, the title compound 236 wasobtained in 11% yield. ¹H NMR: (CD₃OD) δ (ppm): 7.89 (d, J=8.2 Hz, 2H),7.45 (d, J=8.2 Hz, 2H), 7.28 (d, J=8.5 Hz, 1H), 7.19-7.06 (m, 3H),6.93-6.79 (m, 3H), 4.55 (s, 2H), 4.18 (t, J=6.3 Hz, 2H), 3.65-3.62 (m,4H), 2.51 (t, J=6.6 Hz, 2H), 2.46-2.42 (m, 4H).

Example 148

Step 1: 4-Morpholin-4-yl-benzoic acid methyl ester (237):

A flame-dried pressure vessel was charged with cesium carbonate (912 mg,2.80 mmol) and toluene (8 mL) and the flasked was purged with nitrogen.Palladium acetate (9.0 mg, 0.004 mmol) andrac-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (37 mg, 0.06 mmol). Themixture was degassed and heated at 100° C. for 18 h. It was allowed tocool to room temperature and was filtered through celite, rinsed withethyl acetate and partitioned between ethyl acetate and water. Theorganic layer was washed with a saturated solution of NaHCO₃, brine,dried over MgSO₄ and concentrated in vacuo to afford the title compound237 (443 mg, 100% yield). ¹H NMR: (CDCl₃) δ (ppm):8.02 (d, J=9.2 Hz,2H), 6.95 (d, J=8.8 Hz, 2H), 3.95 (s, 4H), 3.92 (s, 3H), 3.38-3.35 (m,4H).

Step 2: N-(2-Amino-phenyl)-4-morpholin-4-yl-benzamide (238):

Following the procedure described in Example 1, step 4, 5 butsubstituting the previous compound for 6, the title compound 238 wasobtained in 33% yield. ¹H NMR: (DMSO-d₆) δ (ppm): 7.20 (d, J=7.9 Hz,1H), 7.07 (d, J=8.8 Hz, 2H), 7.01 (t, J=7.0 Hz, 1H), 6.83 (d, J=7.9 Hz,1H), 6.65 (t, J=7.5 Hz, 1H), 4.90 (s, 2H), 3.81-3.79 (m, 4H), 3.32-3.28(m, 4H).

Example 149

Step 1: 3-Methylsulfanyl-3-(pyridin-4-ylamino)-acrylonitrile (239)

To a solution of pyridin-4-ylamine (1.0 g, 11.0 mmol) and3,3-Bis-methylsulfanyl-acrylonitrile (2.05 g, 12.6 mmol) in DMF at roomtemperature, was added powdered 4A molecular sieves. The mixture wasstirred for 1 hr. Subsequently the mixture was cooled to 0° C., 60% NaHdispersion in oil (0.92 g, 23.0 mmol) was added portionwise over 1 hr.and it was stirred at 0° C. for an additional 2 hrs. The cold bath wasremoved and the mixture was stirred at room temperature for 20 hrs. DMFwas removed in vacuo and the crude was purified by column chromatography(gradient of EtOAc to 25% MeOH/EtOAc) to afford the desired product asan off-white solid (1.9 g, 89%).

Step 2:N-(2-Amino-phenyl)-4-{[2-cyano-1-(pyridin-4-ylamino)-vinylamino]-methyl}-benzamide(240)

To a mixture of 3-methylsulfanyl-3-(pyridin-4-ylamino)-acrylonitrile(0.2 g, 1.0 mmol), 4-aminomethyl-benzoic acid (0.173 g, 1.14 mmol), DMAP(1 mg) and Et₃N (0.14 ml, 1.0 mmol) was added dry pyridine (0.5 ml). Theresulting stirring mixture was heated to 55° C. for 4.5 hrs., additionalEt₃N (0.14 ml) was added and mixture was heated from 75° C. to 90° C.over a period of ˜30 hrs. When the reaction was complete, pyridine waspartially removed in vacuo and the crude was purified by columnchromatography (gradient of EtOAc to 20% MeOH/EtOAc) to afford thedesired product as an off-white solid (130 mg, 44%).

Following the procedure described in Example 1, step 4, 5 butsubstituting the previous compound for 6, the title compound 240 wasobtained in 33% yield. ¹H NMR: ¹H NMR: (300 MHz, DMSO-d₆) δ (ppm): 9.69(br, 2H), 8.48 (br, 3H), 8.03 (d, J=7.9 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H),7.29 (br, 2H), 7.23 (d, J=7.9 Hz, 1H), 7.03 (t, J=7.0 Hz, 1H), 6.84 (d,J=7.9 Hz, 1H), 6.65 (t, J=7.3 Hz, 1H), 4.96 (br, 2H), 4.62 (d, J=5.7 Hz,2H).

Example 150

Step 1: 4-[(2-Chloro-9H-purin-6-ylamino)-methyl]-benzoic acid methylester (241)

A suspension of 2,6-dichloro-9H-purine (1 g, 5.29 mmol),4-aminomethyl-benzoic acid methyl ester hydrochloride (1.2 equiv., 1.28g) and NaHCO₃ (2.1 equiv., 935 mg) in water was heated at 100° C. Thehomogeneous solution thus formed was refluxed 30 min. The resultingwhite precipitate was filtered, washed with cold water and dried undervacuum giving the title compound 241 (1 g, 3.14 mmol, 60%). LRMScalc:317.7, found: 318.3 (MH)⁺.

Step 2:4-{[2-Chloro-9-(2-methoxy-ethyl)-9H-purin-6-ylamino]-methyl}-benzoicacid methyl ester (242)

Following the procedure described in Example 144, step 2 butsubstituting the previous compound for 2-amino-6-methoxybenzothiazole,the title compound 242 was obtained in 41% yield.

Step 3:N-(2-Amino-phenyl)-4-{[2-chloro-9-(2-methoxy-ethyl)-9H-purin-6-ylamino]-methyl}-benzamide(243):

Following the procedure described in Example 1, step 4, 5 butsubstituting the previous compound for 6, the title compound 243 wasobtained in 85% yield. ¹H NMR (CDCl₃) δ (ppm): 9.64 (s, 1H), 8.94 (bs,1H), 8.18 (s, 1H), 7.96 (d, J=7.8 Hz, 2H), 7.52 (d, J=7.8 Hz, 2H), 7.21(d. J=7.7 Hz, 1H), 7,01 (dd, J=7.3, 8.0 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H),6.62 (dd, J=7.3, 7.7 Hz, 1H), 4.91 (bs, 2H), 4.78 (bs, 2H), 4.18 (m,2H), 3.70 (m, 2H), 3.26 (s, 3H)

Example 151

Step 1:Methyl-4-{[3-(2-chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-amino-methyl}-benzoicacid ester (244)

To a stirred suspension at 0° C. of methyl 4-(aminomethyl)benzoate.HCl 2(809 mg, 4.01 mmol) in anhydrous CH₂Cl₂ (25 ml) under nitrogen weresuccessively added i-Pr₂NEt (1.91 ml, 10.95 mmol) and3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride (1.00g, 3.65 mmol). After 45 min, the reaction mixture was allowed to warm upto room temperature for 3 h. Then, the reaction mixture wasconcentrated, diluted with AcOEt, and successively washed with sat.NH₄Cl, H₂O, sat. NaHCO₃, H₂O and brine, dried over anhydrous MgSO₄,filtered and concentrated to afford the title compound 244 (1.50 g,quantitative yield) as a colorless sticky foam. ¹H NMR (300 MHz, CDCl₃)δ (ppm): 7.93 (d, J=7.9 Hz, 2H), 7.46-7.35 (m, 1H), 7.29 (d, J=8.4 Hz,1H), 7.15-7.05 (m, 3H), 5.49 (bs, 1H), 4.46 (d, J=5.7 Hz, 2H), 3.92 (s,3H), 2.80 (s, 3H).

Step 2:4-{[3-(2-Chloro-6-fluoro-phenyl)-5-methyl-isoxazole4-carbonyl]-amino-methyl}-benzoicacid (245)

To a stirred solution at room temperature of 244 (1.45 g, 3.60 mmol) inTHF (20 ml) was added a solution of LiOH.H₂O (453 mg, 10.80 mmol) inwater (20 ml). After 20 h, the reaction mixture was concentrated,diluted with water and acidified with 1N HCl until pH 6 in order to geta white precipitate. After 10 min, the suspension was filtered off andthe cake was abundantly washed with water, and dried to afford the titlecompound 245 (1.23 g, 3.15 mmol, 88% yield) as a white solid. ¹H NMR(300 MHz, DMSO-d₆) δ (ppm): 8.69 (t, J=5.9 Hz, 1H), 7.91 (d, J=7.9 Hz,2H), 7.70-7.58 (m, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.45-7.30 (m, 3H), 4.44(d, J=5.7 Hz, 2H), 2.72 (s, 3H).

Step 3:4-(9-Chloro-3-methyl-4-oxo-4H-isoxazolo[4,3-c]quinolin-5-ylmethyl)-benzoicacid (246)

To a stirred suspension at room temperature of 245 (795 mg, 2.05 mmol)in anhydrous DMF (10 ml) was added a solution of NaOH (409 mg, 10.22mmol) in anhydrous MeOH (5.1 ml). Then, the reaction mixture was warmedup to 40° C. After 3 days, the reaction mixture was concentrated,diluted with water and acidified with 1N HCl until pH 5 in order to geta pale pinky precipitate. After 30 min, the suspension was filtered offand the cake was abundantly washed with water, and dried to afford thetitle compound 246 (679 mg, 1.84 mmol, 90% yield) as a pale pinky solid.¹H NMR (300 MHz, DMSO-d₆) δ (ppm): AB system (δ_(A)=7.92, δ_(B)=7.40,J=8.4 Hz, 4H), 7.56 (t, J=8.1 Hz, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.31 (d,J=8.3 Hz, 1H), 5.59 (bs, 2H), 2.95 (s, 3H).

Step 4:N-(2-Amino-phenyl)-4-(9-chloro-3-methyl4-oxo-4H-isoxazolo[4,3-c]quinolin-5-ylmethyl)-benzamide(247)

The title compound 247 was obtained from 246 in one step following thesame procedure as Example 1, steps 5. ¹H NMR (300 MHz, DMSO-d₆) δ (ppm):9.65 (s, 1H), AB system (δ_(A)=7.95, δ_(B)=7.42, J=8.1 Hz, 4H), 7.58 (t,J=8.1 Hz, 1H), 7.48 (d, J=7.5 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.17 (d,J=7.5 Hz, 1H), 7.00 (t, J=7.3 Hz, 1H), 6.80 (d, J=7.5 Hz, 1H), 6.62 (t,J=7.3 Hz, 1H), 5.61 (bs, 2H), 4.91 (s, 2H), 2.97 (s, 3H).

Example 152

Step 1: 4-(1H-Imidazol-2-yl-(benzoic acid (248)

To a stirred solution of 4-formylbenzoic acid (2.00 g, 12.3 mmol) inammonium hydroxide (9 ml) was added glyoxal (2.86 ml, 20.0 mmol). Thereaction mixture was stirred 16 h at room temperature. 1N HCl was addedto the reaction mixture to acidify to pH 5. The solvent was evaporatedand the residue was triturated 30 min. in water (20 ml) and filtered toobtain the title compound 248 (2.08 g, 83%) as a white solid. LRMS:188.1 (Calc.); 189.1 (found).

Step 2: N-(2-Amino-phenyl)-4-(1H-imidazol-2-yl)-benzamide (249)

The title compound 249 was obtained following the same procedure asExample 1, step 5. ¹H NMR (CDCl₃) δ (ppm): ¹H NMR: (DMSO) δ (ppm): 9.72(bs, 1H), 8.07 (s, 4H), 7.26 (s, 2H), 7.18 (d, J=7.9 Hz, 1H), 6.98 (dd,J=7.5, 7.5 Hz, 1H), 6.79 (d, J=7.9 Hz, 1H), 6.60 (dd, J=7.5, 7.5 Hz,1H). MS: (calc.) 278.1; (obt.) 279.1 (MH)⁺.

Example 153

Step 1: 4-Thiocarbamoylmethyl-benzoic acid (250)

To a stirred suspension of 4-cyanomethyl-benzoic acid (1.65 g, 10.24mmol) and Et₃N (5 ml) in pyridine, H₂S was bubbled during 3 h. Thereaction mixture was stirred 16 h at room temperature. Water was thenadded to the reaction mixture which was agitated for 1 h beforeacidifying to pH 6 with 1M HCl. The solvent was evaporated and theresidue was triturated 30 min. in water (20 ml) and filtered to obtainthe title compound 250 (2.08 g, 83%) as a white solid. ¹H NMR (DMSO) δ(ppm): 12.85 (bs, 1H), 9.53 (bs, 1H), 9.43 (bs, 1H), 7.88 (d, J=8.1 Hz,2H), 7.44 (d. J=8.1 Hz, 2H), 3.88 (s, 2H).

Step 2: 4-(4-Chloromethyl-thiazol-2-ylmethyl)-benzoic acid (251)

A solution of 250 (729 mg, 3.73 mmol) and 1,3-dichloroacetone (474 mg,3.73 mmol) in THF (30 ml) was stirred at 40° C. during 48 h. The solventwas evaporated then the residue was dissolved in ethyl acetate, washedwith brine, dried over anhydrous MgSO₄, filtered and concentrated. Thecrude residue was purified by flash chromatography on silica gel (2-4%MeOH/CH₂Cl₂) to afford the title compound (827 mg, 83% yield) as a whitesolid. ¹H NMR (DMSO) δ (ppm): 12.93 (bs, 1H), 7.91 (d, J=8.1 Hz, 2H),7.63 (s, 1H), 7.46 (d, J=8.1 Hz, 2H), 4.78 (s, 2H), 4.42 (s, 2H).

Step 3:N-(2-Amino-phenyl)-4-(4-morpholin-4-ylmethyl-thiazol-2-ylmethyl)-benzamide(252)

K₂CO₃ (599 mg, 4.33 mmol) was added to a solution of 251 (527 mg, 1.97mmol) an morpholine (189

l, 2.17 mmol) in THF (15 ml) was refluxed during 48 h. The solvent wasevaporated. The crude residue was purified by flash chromatography onsilica gel (3-50% MeOH/CH₂Cl₂) to afford the title compound 252 (238 mg,38% yield) as a pale yellow solid. LRMS: 318.2 (calc) 319.2 (found).

The title compound 252 was obtained following the same procedure asExample 1, step 5. ¹H NMR (DMSO) δ (ppm): 9.63 (bs, 1H), 7.94 (d, J=8.1Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 7.33 (s, 1H), 7.15 (d, J=8.1 Hz, 1H),6.97 (dd, J=7.7, 7.7 Hz, 1H), 6.77 (d, J=7.3 Hz, 1H), 6.59 (dd, J=8.1,8.1 Hz, 1H), 4.90 (bs, 2H), 4.40 (s, 2H), 3.59-3.56 (m, 6H), 2.44-2.38(m, 4H). LMRS: 408.2 (calc) 409.2 (found).

Example 154

Step 1: Methyl3-[3-(4-methoxycarbonyl-benzyl)-ureido]-thiophene-2-carboxylate (253)

The procedure described by Nakao (K. Nakao, R. Shimizu, H. Kubota, M.Yasuhara, Y. Hashimura, T. Suzuki, T. Fujita and H. Ohmizu; Bioorg. Med.Chem. 1998, 6, 849-868.) was followed to afford the title compound 253(1.01 g, 91%) as a yellow solid. ¹H NMR (CDCl₃) δ (ppm): 9.55 (bs, 1H),8.00-7.97 (m, 3H), 7.42-7.37 (m, 3H), 5.45 (t, J=5.8 Hz, 1H), 4.52 (d,J=6.0 Hz, 2H), 3.91 (s, 3H), 3.82 (s, 3H).

Step 2:4-(2,4-Dioxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-ylmethyl)benzoicacid (254)

To a suspension of 253 (422 mg, 1.21 mmol) in MeOH (15 ml) was addedNaOH (145 mg, 3.63 mmol). The reaction mixture was heated at 60° C.during 16 h. Water (1 ml) was then added and the reaction mixture wasstirred for 1 more hour. The solvent was evaporated and the residue wasdissolved in water and acidified to pH 5 with HCl 1M. The precipitatewas filtered to afford the desired compound 254 (348 mg, 95%) as a whitesolid. LRMS: 302.0 (Calc.); 303.0 (found).

Steps 3:N-(2-Amino-phenyl)-4-(1-ethyl-2,4-dioxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-ylmethyl)-benzamide(255)

The title compound 255 was obtained as a yellow solid (73%) followingthe same procedure as Example 99, step 2, 3, then followed by Example 1,step 5. ¹H NMR: (DMSO) δ (ppm): 9.61 (bs, 1H, NH), 8.22 (d, J=5.5 Hz,1H, CH), 7.91 (d, J=8.2 Hz, 2H, CH), 7.43-7.40 (m, 3H, CH), 7.15 (d,J=7.4 Hz, 1H, CH), 6.96 (dd, J=7.6, 7.6 Hz, 1H, CH), 6.77 (d, J=7.1 Hz,1H, CH), 6.59 (dd, J=7.4, 7.4 Hz, 1H, CH), 5.17 (s, 2H, NCH₂), 4.88 (bs,2H, NH₂) 4.09 (q, J=7.0, 2H, CH₂), 1.22 (t, J=7.0, 3H, CH₃). LRMS: 420.1(calc.); 421.0 (found).

Example 155

Step 1: 3H-Thieno[3,2-d]pyrimidin-4-one (256)

Methyl-3-amino-2-thiophene carboxylate (510 mg, 3.24 mmol) was dissolvedin formamide (20 ml) and heated at 170° C. 16 h. The solvent wasevaporated. The crude residue was then purified by flash chromatographyon silica gel (2-4% MeOH/CH₂Cl₂) to afford the title compound 256 (157mg, 32% yield). LRMS: 152.0 (Calc.); 152.9 (found).

Step 2:N-(2-Aminophenyl)-4-(4-oxo-4H-thieno[3,2-d]pyrimidin-3-ylmethyl)-benzamide(257)

Following the procedure described in Example 85, step 1 but substitutingthe previous compound for 119, followed by Example 1, step 4, 5, thetitle compound 257 was obtained in 41% yield. ¹H NMR: (DMSO) δ (ppm):9.61 (bs, 1H), 8.70 (s, 1H), 8.22 (dd, J=5.2, 0.5 Hz, 1H), 7.95 (d,J=8.2 Hz, 2H), 7.47 (d, J=8.5 Hz, 2H), 7.44 (dd, J=5.2, 0.6 Hz, 1H),7.15 (d, J=7.7 Hz, 1H), 6.96 (dd, J=6.9, 6.9 Hz, 1H), 6.77 (d, J=7.1Hz,1H), 6.58 (dd, J=7.0, 7.0 Hz, 1H), 5.31 (s, 2H), 4.87 (bs, 2H). MS:376.1 (calc.); 377.1 (found).

Example 156

Step 1: Methyl 2-amino4,5-dimethyl-thiophene-3-carboxylate (258)

The procedure described by Hozien (Z. A. Hozien, F. M. Atta, Kh. M.Hassan, A. A. Abdel-Wahab and S. A. Ahmed; Synht. Commun. 1996, 26(20),3733-3755.) was followed to afford the title compound 258 (1.44 g, 17%)as a yellow solid. LRMS: 197.1 (Calc.); 200.1 (found).

Steps 2:N-(2-Amino-phenyl)-4-(5,6-dimethyl-4-oxo-4H-thieno[2,3-d]pyrimidin-3-ylmethyl)-benzamide(259)

Following the procedure described in Example 155, step 1, 2 butsubstituting 258 for 256, the title compound 259 was obtained as a whitesolid (55%). ¹H NMR: (DMSO) δ (ppm): 9.61 (bs, 1H), 8.57 (s, 1H), 7.94(d, J=8.0 Hz, 2H), 7.45 (d, J=7.7 Hz, 2H), 7.16 (d, J=7.7 Hz, 1H), 6.96(dd, J=7.6, 7.6 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 6.59 (dd, J=7.4, 7.4Hz, 1H), 5.25 (s, 2H), 4.87 (bs, 2H), 2.39 (s, 3H), 2.37 (s, 3H). LRMS:404.1 (calc); 405.0 (found).

Example 157

Step 1: Methyl 4-(4-oxo-chroman-3-ylidenemethyl)-benzoate (260)

Concentrated H₂SO₄ (2 ml) was slowly added to a solution of 4-chromanone(2.00 g, 13.50 mmol) and methyl4-formylbenzoate (2.11 g, 12.86 mmol) inglacial acetic acid. The reaction mixture was stirred 16 h at roomtemperature. The solvent was concentrated to half volume the resultingprecipitate was filtered and rinsed with ethyl acetate to afford thetitle compound 260 (3.11 g, 82%) as a purple solid. ¹H NMR: (DMSO) δ(ppm): 8.05 (d, J=8.2 Hz, 2H), 7.90 (d, J=7.6 Hz, 1H), 7.79 (s, 1H),7.64-7.59(m, 3H), 7.15 (dd, J=7.6, 7.6 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H),5.43 (s, 2H), 3.89 (s, 3H).

Step 2: Methyl-4-(4-oxo-4H-chromen-3-ylmethyl)-benzoate (261)

Water (0.2 ml) and RhCl₃.H₂O (7 mg, 0.034 mmol) was added to asuspension of compound 260 (200 mg, 0.680 mmol) in EtOH (2 ml) and CDCl₃(2 ml). The reaction mixture was stirred 16 h at 70° C. The reactionmixture was cooled down and diluted in ethyl acetate, washed with brine,dried over anhydrous MgSO₄, filtered and concentrated. The crude residuewas then purified by flash chromatography on silica gel (0.5-1%MeOH/CH₂Cl₂)to afford the title compound 261 (118 mg, 59%) as a whitesolid. ¹H NMR: (DMSO) δ (ppm): 8.45 (s, 1H), 8.03 (dd, J=7.9, 1.8 Hz,1H), 7.87 (d, J=8.4 Hz, 2H), 7.83-7.77(m, 1H), 7.65 (d, J=8.3 Hz, 1H),7.50-7.43 (m3, 1H), 3.82 (s, 3H), 3.80 (s, 2H).

Step 3: N-(2-Amino-phenyl)-4-(4-oxo-4H-chromen-3-ylmethyl)-benzamide(262)

The title compound 262 was obtained following the same procedure asExample 1, step 4, 5. ¹H NMR: (DMSO) δ (ppm): 9.56 (bs, 1H), 8.45 (s,1H), 8.04 (d, J=7.9 Hz, 1H), 7.88 (d, J=8.4 Hz, 2H), 7.80 (dd, J=7.5,7.5 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.51-7.42 (m, 3H), 7.14 (d, J=7.9Hz, 1H), 6.96 (dd, J=7.3, 7.3 Hz, 1H), 6.76 (d, J=7.9 Hz, 1H), 6.58 (dd,J=7.3, 7.3 Hz, 1H), 4.86 (bs, 2H), 3.80 (s, 2H). LRMS: 370.1 (calc.);371.1 (found).

Example 158

Step 2: Methyl 4-chroman-3-ylmethyl-benzoate (263)

Pd/C 10% was added to a suspension of 260 (200 mg, 0.68 mmol) in MeOH(40 ml) and DMA (10 ml) which was previously purged under vacuum. Thereaction mixture was stirred during 4 h at room temperature. Afterevaporation of the MeOH, water was added to the oily residue and theprecipitate obtained was filtered. The crude residue was then purifiedby flash chromatography on silica gel (5-8% AcOEt/Hex)to afford thetitle compound 263 (114 mg, 59%) as a white solid. LRMS: 282.1 (Calc.);283.0 (found).

Step 3: N-(2-Amino-phenyl)-4-chroman-3-ylmethyl-benzamide (265)

The title compound 265 was obtained following the same procedure asExample 1, steps 4 and 5. ¹H NMR: (acetone) δ (ppm): 9.06 (bs, 1H), 8.01(d, J=7.9 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.31 (d, J=7.9 Hz, 1H),7.08-6.98 (m, 3H), 6.87 (d, J=7.5 Hz, 1H),6.82-6.66 (m, 3H), 4.62 (s,2H), 4.22-4.17 (m, 1H), 4.88-3.81 (m, 1H), 2.88-2.71 (m, 3H), 2.61-2.53(m, 1H), 2.41-2.53 (m, 1H). LRMS: 358.2 (calc.); 359.1 (found).

Example 159

Step 2: Methyl 4-(4-oxo-chroman-3-ylmethyl)-benzoate (264)

A suspension of 260 (400 mg, 1.36 mmol) and benzenesulfonyl hydrazine(702 mg, 4.08 mmol) in DMF (7 ml) was stirred at 100° C. during 48 h.The solvent was evaporated and the residue was diluted in AcOEt, washedwith NH₄Cl sat., brine, dried over anhydrous MgSO₄, filtered andconcentrated. The crude residue was then purified by flashchromatography on silica gel (5% AcOEt/HEx)to afford the title compound264 (170 mg, 42%) as a white solid. LRMS: 296.1 (Calc.); 297.0 (found).

Step 3: N-(2-Amino-phenyl)-4-(4-oxo-chroman-3-ylmethyl)-benzamide (266)

The title compound 266 was obtained following the same procedure asExample 1, steps 4 and 5. ¹H NMR: (acetone) δ (ppm): 9.62 (bs, 1H), 7.93(d, J=7.9 Hz, 2H), 7.79 (d, J=7.9 Hz, 1H), 7.58 (dd, J=7.0, 7.0 Hz, 1H),7.39 (d, J=7.9 Hz, 2H), 7.17-7.04 (m, 3H), 6.97 (dd, J=7.0, 7.0 Hz, 1H),6.78 (d, J=7.9 Hz, 1H), 6.60 (dd, J=7.5, 7.5 Hz, 1H), 4.88 (s, 2H),4.44-4.39 (m, 1H), 4.28-4.21 (m, 1H), 2.26-3.21 (m, 2H), 2.83-2.74 (m,1H). LRMS: 372.1 (cacl.); 372.1 (found).

Example 160

Step 1: Methyl4(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)-benzoate (266)

Et₃N (3.18 ml, 22.8 mmol) was added to a stirring solution of2-H-1,4-benzoxazin-3-(4H)one (2.50 g, 16.8 mmol) and methyl4-formylbenzoate (4.59 g, 27.5 mmol) in Ac₂O (20 ml). The reactionmixture was refluxed 16 h. After this mixture was cooled for 3 days, thesolid was filtered and rinsed with ethyl acetate to afford the titlecompound 266 (657 mg, 13%) as a yellow solid. LRMS: 295.1 (Calc.); 296.0(found).

Step 2: Methyl4-(3-oxo-3,4-dihydro-benzo[1,4]oxazin-2-ylidenemethyl)-benzoate (267)

The title compound 267 was obtained following the same procedure asExample 158, step 2. LRMS: 297.1 (Calc.); 298.1 (found).

Step 3:N-(2-Amino-phenyl)-4-(4-ethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)-benzamide(269)

The title compound 269 was obtained from 267 following the sameprocedure as Example 99, step 2, 3, then followed by Example 1, step 4,5. ¹H NMR: (DMSO) δ (ppm): 9.61 (bs, 1H), 7.91 (d, J=7.9 Hz, 2H), 7.39(d, J=7.9 Hz, 2H), 7.22 (d, J=7.9 Hz, 1H), 7.17 (d, J=7.5 Hz, 1H),7.11-6.91 (m, 4H), 6.77 (d, J=7.0 Hz, 1H), 6.60 (dd, J=7.0, 7.0 Hz, 1H),4.95-4.91 (m, 1H), 4.89 (bs, 2H), 3.95 (q, J=7.0 Hz, 2H), 3.28-3.22 (m,1H), 3.17-2.89 (m, 1H), 1.16 (t, J=7.0 Hz, 3H). LRMS: 401.2 (calc.);402.1 (obt.).

Example 161

Step 1:N-(2-Amino-phenyl)-4-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)-benzamide(270)

The title compound 270 was obtained from 267 following the sameprocedure as Example 1, step 4, 5. ¹H NMR: (DMSO) δ (ppm): 10.74 (bs,1H), 9.61 (bs, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.41 (d, J=7.9 Hz, 2H), 7.17(d, J=7.5 Hz, 1H), 6.99-6.85 (m, 5H), 6.78 (d, J=7.5 Hz, 1H), 6.60 (dd,J=7.0, 7.0 Hz, 1H), 4.92-4.89 (m, 3H), 3.29-3.23 (m, 1H), 3.15-3.07 (m,1H). MS: (calc.) 373.1; (obt.) 374.1 (MH)⁺.

Example 162

Step 1: Methyl 4-(1-oxo-indan-2-ylmethyl)-benzoate (271)

A 2M LDA solution in THF (4.16 ml, 8.32 mmol) was added to a solution ofindanone (1.00 g, 7.57 mmol) in THF (10 ml) at −60° C. The solution wasslowly warmed to 0° C. during a period of 15 min. and was agitated for15 more min. The reaction was then cooled to −78° C. and a solution ofmethyl-4-bromobenzoate (1.73 g, 7.57 mmol) was slowly added. Thesolution was slowly warmed to −20° C. and stirred during 4 hours. Thereaction mixture was quenched with HCL 1M and the solvent wasevaporated. The residue was diluted in ethyl acetate, washed with brine,dried over anhydrous MgSO₄, filtered and concentrated. The crude residuewas then purified by flash chromatography on silica gel (5-20%AcOEt/HEx)to afford the title compound 271 (245 mg, 17%) as a whitesolid. LRMS: 280.1 (Calc.); 281.1 (found).

Step 2: N-(2-Amino-phenyl)-4-(1-oxo-indan-2-ylmethyl)-benzamide (272)

The title compound 272 was obtained following the same procedure asExample 1, step 4, 5. ¹H NMR: (DMSO) δ (ppm): 9.59 (bs, 1H), 7.91 (d,J=7.6 Hz, 2H), 7.69-7.64 (m, 2H), 7.54 (d, J=7.6 Hz, 1H), 7.45-7.40 (m,3H), 7.16 (d, J=8.2 Hz, 1H), 6.96 (dd, J=7.3, 7.3 Hz, 1H), 6.77 (d,J=8.2 Hz, 1H), 6.59 (dd, J=7.3, 7.3 Hz, 1H), 4.87 (bs, 2H), 3.23-3.14(m, 3H), 2.85-2.81 (m, 2H). LRMS: 356.1 (calc.); 357.2 (found).

Example 163

Step 1: 4-(1-Oxo-indan-2-ylidenemethyl)-benzoic acid (273)

To a suspension of indanone (2.00 g, 15.1 mmol) and4-carboxybenzaldehyde (1.89 g, 12.6 mmol) in EtOH (10 ml) was added KOH(1.77 g, 31.5 mmol) at 0° C. The reaction mixture was stirred 30 min at0° C. then at room temperature for 16 h. The solvent was evaporated andthe residue was dissolved in water, acidified to pH 5 with HCl 1 M. Theprecipitate was filtered and rinsed with water to afford the titlecompound 273 (2.27 g, 57%) as a yellow solid. LPMS: 264.1 (Calc.); 265.0(found).

Step 2: N-(2-Amino-phenyl)-4-(1-oxo-indan-2-ylidenemethyl)-benzamide(274)

The title compound 274 was obtained following the same procedure asExample 1, step 5. LRMS: 354.1 (Calc.); 355.0 (found).

Step 3: N-(2-Amino-phenyl)4-(1-hydroxy-indan-2-ylmethyl)-benzamide (275)

To a suspension of 274 (300 mg, 0.85 mmol) in MeOH (8 ml) and water (1ml) was added NaBH₄ (75 mg, 1.95 mmol). The reaction mixture was stirredat 50° C. 16 h and cooled down. Water was added to the solution and theprecipitated was filtered and rinsed with cold water to afford the titlecompound 275 (224 mg, 74%) as a white solid. ¹H NMR: (acetone) δ (ppm):9.05 (bs, 1H), 8.00 (dd, J=8.2, 2.7 Hz, 2H), 7.47 (d, J=8.5 Hz, 1H),7.43 (d, J=8.2 Hz, 1H), 7.38-7.30 (m, 2H), 7.22-7.12 (m, 3H), 7.01 (ddd,J=7.6, 7.6, 1.5 Hz, 1H), 6.87 (dd, J=8.0, 1.1 Hz, 1H), 6.68 (dd, J=7.6,7.6 Hz, 1H), 4.98 (t, J=5.8 Hz, 0.4H), 4.89 (t, J=6.7 Hz, 0.6H), 4.63(bs, 2H), 4.45 (d, J=6.9 Hz, 0.6H), 4.06 (d, J=6.0 Hz, 0.4H), 3.30-3.19(m, 1H), 2.88-2.48 (m, 3H, CH₂). LRMS: 358.2 (calc.); 359.1 (found).

Example 164

Step 1: 4-(3.5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl)-benzoic acid(276)

To a solution of NaH (60% in mineral oil, 250 mg, 6.3 mmol) at 0° C.acetyl acetone (0.646 ml, 6.3 mmol) was added followed by4-bromomethyl-benzoic acid methyl ester 2 (1.2 g, 5.2 mmol). Thereaction mixture stirred 1 hour at room temperature and refluxed for 2hours. Phenyl hydrazine (0.51 ml, 5.2 mmol) was added and the reactionmixture refluxed for an additional hour. THF was removed in vacuum andthe oily residue was partitioned between water and ethyl acetate.Organic layer was separated, dried, evaporated and purify bychromatography on a silica gel column, eluent EtOAc-hexane (1:1) toproduce an oily material (800 mg) which was treated with a solution ofNaOH (0.8 g, 20 mmol) in 20 ml water for 1 hour at room temperature. Thefollowing steps, acidification with HCl (pH 6), extraction of theresultant emulsion with ethyl acetate, drying the extract with sodiumsulfate, evaporation and column chromatography (eluent EtOAc-hexane,1:1) afforded 390 mg of a mixture of 276 (the title compound) and 278(molar ratio 1:2) [M−1]⁺ 307.0 and 191.1 This mixture was taken for thenext step as is.

Step 2.N-(2-Amino-phenyl)-4-(3,5-dimethyl-1-phenyl-1H-pyrazol4-ylmethyl)-benzamide(277)

Following a procedure analogous to that described in Example 92, step 2,but substituting 276 for 143, the title compound 277 was obtained in 25%yield (purified by chromatography using as eluent EtOAc-hexane, 1:1). ¹HNMR: (300 MHz, DMSO-d₆, δ (ppm): 9.64 (s, 1H); 7.97 (d, J=7.6 Hz, 2H),7.42-7.56 (m, 5H), 7.37 (d, J=8.2 Hz, 2H), 7.22 (d, J=7.6 Hz, 1H), 7.03(t, J=7.6 Hz, 1H), 6.84 (d, J=8.2 Hz, 1H), 6.66 (t, J=7.6 Hz, 1H), 4.93(s, 2H), 3.92 (s, 2H), 2.34 (s, 3H), 2.18 (s, 3H).

Example 165

Step 1: 4-(3-Oxo-butyl)-benzoic acid (278)

To a solution of acetyl acetone (5.0 ml, 49 mmol) at room temperatureNaOMe (25% wt, 10.8 ml, 47.3 mmol) was added followed by4-bromomethyl-benzoic acid methyl ester 2 (9.0 g, 39.3 mmol). Thereaction mixture refluxed 3 hours, cooled to the room temperature andacidified with HCl (pH 1-2). Evaporation of the resultant solutionyielded a residue, which was refluxed in a mixture of glacial AcOH (50ml) and conc. HCl (25 ml) for 4 hours. Acids were removed in vacuum andthe residue was triturated with water to form a crystalline material,which was collected by filtration and dried to afford 278 (6.72 g, 80%yield). [M−1] 191.1.

Step 2. 4-(5-Amino-4-cyano-3-methyl-thiophen-2-ylmethyl)-benzoic acid279

To a refluxing suspension of 4-(3-oxo-butyl)-benzoic acid 278 (700 mg,3.65 mmol), malonodinitrile (241 mg, 3.65 mmol) and sulfur (130 mg, 3.65mmol) in 20 ml EtOH, diethylamine (0.5 ml, 4.8 mmol) was added. Thereaction mixture refluxed 1 hour, cooled to the room temperature,acidified with conc. HCl (pH 4-5) and evaporated to yield a solidresidue. This material was partitioned between water and ethyl acetate,organic layer was separated, dried, evaporated and chromatographed on asilica gel column, eluent EtOAc-hexane, 1:1, to afford the titlecompound 279 (300 mg, 30% yield). ¹H NMR: (300 MHz, DMSO-d₆, δ ppm):7.87 (d, J=8.4 Hz, 2H), 7.29 (d, J=7.9 Hz, 2H), 6.98 (s, 2H), 3.92 (s,2H), 2.03 (s, 3H).

Step 3. 4-(5-Acetylamino-4-cyano-3-methyl-thiophen-2-ylmethyl)-benzoicacid 280

To a solution of4-(5-amino-4-cyano-3-methyl-thiophen-2-ylmethyl)-benzoic acid 279 (230mg, 0.86 mmol) in a solvent mixture acetone (5 ml)-dichloromethane (5ml) at room temperature acetyl chloride (0.305 ml, 4.3 mmol) was added.After 2 hours of stirring at the same conditions a precipitate of thetitle compound 280 formed which was collected and dried (200 mg, 75%yield). [M−1] 313.1.

Step 4:N-(2-Amino-phenyl)4-(5-acetylamino-4-cyano-3-methyl-thiophen-2-ylmethyl)-benzamide(281)

Following a procedure analogous to that described in Example 92, step 2,but substituting 280 for 143, the title compound 281 was obtained in 25%yield. 1H NMR (DMSO) δ (ppm): 9.61 (s, 1H); 7.91 (d, J=7.9 Hz, 2H), 7.34(d, J=8.4 Hz, 2H), 7.15 (d, J=7.5 Hz, 1H), 6.96 (t, J=6.6 Hz, 1H), 6.77(d, J=7.0 Hz, 1H), 6.59 (t, J=7.9 Hz, 1H), 4.89 (s, 2H), 4.10 (s, 2H),2.19 (s, 3H), 2.16 (s, 3H). [M+1] 405.0.

Example 166

Step 1. 4-(N-Hydroxycarbamimidoylmethyl)-benzoic acid (282)

A suspension of 4-cyanomethyl benzoic acid (2.07 g, 12.86 mmol),NH₂OH.HCl (1.79 g, 25.71 mmol) and potassium hydroxide (2.16 g, 38.57mmol) in 70 ml ethanol refluxed for 36 hours, poured into 100 ml waterand acidified with conc. HCl (pH 5-6). EtOH was removed in vacuum andthe remaining suspension was treated with another 100 ml water. Aprecipitate formed which was collected and dried to afford the titlecompound 282. [M+1]195.1.

Step 2. 4-(5-Methyl-[1,2,4]oxadiazol-3-ylmethyl)-benzoic acid (283)

A solution of 4N-hydroxycarbamimidoylmethyl)-benzoic acid 282 (388 mg,2.0 mmol) in pyridine (8 ml) was treated with acetic anhydride (0.283ml, 3.0 mmol). The resultant solution refluxed 6 hours, evaporated invacuum and the remaining solid was triturated with water, collected byfiltration, dried and purified by chromatography on a silica gel column,eluent EtOAc, EtOAc-MeOH (10:1) and finally EtOAc-MeOH (1:1), to produce283 (164 mg, 38% yield).[M−1]⁻217.1

Step 3.N-(2-Amino-phenyl)-4-(5-methyl-[1,2,4]oxadiazol-3-ylmethyl)-benzamide(284)

For the preparation of the title compound 284, a procedure analogous tothat described in Example 92, step 2, but substituting 283 for 143, thetitle compound 284 was obtained. ¹H NMR: (DMSO) δ (ppm): 9.62 (s, 1H),7.93 (d, J=7.9 Hz, 2H), 7.42 (d, J=8.4 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H),6.97 (t, J=7.9 Hz, 1H), 6.78 (d, J=7.5 Hz, 1H), 6.60 (t, J=7.9 Hz, 1H),4.92 (s 2H), 4.14 (s, 2H), 2.55 (s, 3H). [M+1]⁺ 309.2

Example 167

Step 1: 4-(3.5-Dimethyl-pyrazol-1-yl)-benzoic acid (285)

A solution of 4-hydrazino-benzoic acid (0.60 g, 3.95 mmol) and acetylacetone (0.405 ml, 3.95 mmol) in ethanol (20 ml) refluxed for 1 hour.Ethanol was removed in vacuum and the remaining solid was trituratedwith water and collected by filtration to produce 285 (0.71 mg, 83%yield). [M−1]⁻ 215.1.

Step 2. N(2-Amino-phenyl)-4-(3,5-dimethyl-pyrazol-1-yl)-benzamide (286)

For the preparation of the title compound 286, a procedure analogous tothat described in Example 92, step 2, but substituting 285 for 143, thetitle compound 286 was obtained in 34% yield (purified by chromatographyusing as eluent CH₂Cl₂-methanol, 19:1). ¹H NMR: (DMSO) δ (ppm): 9.73 (s,1H); 8.09 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 7.17 (d, J=7.5 Hz,1H), 6.98 (t, J=7.0 Hz, 1H), 6.78 (d, J=7.9 Hz, 1H), 6.60 (t, J=7.5 Hz,1H), 6.13 (s, 1H), 4.92 (s, 2H), 2.37 (s, 3H), 2.20 (s, 3H). [M+1]⁺303.3

Example 168

Step 1: 2-(3,4,5-Trimethoxy-phenyl)-2,3-dihydro-furan (287)

To a solution of 5-iodo-1,2,3-trimethoxybenzene (900 mg, 3.06 mmol) and2,3-dihydrofuran (1.16 mL, 15.3 mmol) in dry DMF (8 mL) were added PPh₃(20 mg, 0.077 mmol), KOAc (901 mg, 9.18 mmol), n-Bu₄NCl (850 mg, 3.06mmol) and Pd(OAc)₂ (17 mg, 0.077 mmol). The reaction mixture was stirred18 h at 80° C. The reaction mixture was diluted with AcOEt and water.After separation, the organic layer was washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated. The crude residue was thenpurified by flash chromatography on silica gel (AcOEt/Hexane: 20/80) toafford the title compound 287 (311 mg, 1.32 mmol, 43% yield). ¹H NMR:(300 MHz, CDCl₃) δ (ppm): 6.59 (s, 2H), 6.45 (m, 1H), 5.45 (dd, J=10.5,8.4 Hz, 1H), 4.97 (m, 1H), 3.87 (s, 6H), 3.84 (s, 3H), 3.06 (m, 1H),2.62 (m, 1H).

Step 2: 4-[5-(3,4,5-Trimethoxy-phenyl)-2,5-dihydro-furan-2-yl]-benzoicacid ethyl ester (288)

To a solution of 287 (200 mg, 0.846 mmol) and 4-lodo-benzoic acid ethylester (468 mg, 1.69 mmol) in dry acetonitrile (4 mL) were added PPh₃ (20mg, 0.076 mmol), Ag₂CO₃ (467 mg, 1.69 mmol) and Pd(OAc)₂ (7 mg, 0.03mmol). The reaction mixture was stirred 18 h at 80° C. The reactionmixture was filtered through celite and washed with AcOEt. Water wasadded and the phases were separated. The organic layer was washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated. The cruderesidue was then purified by flash chromatography on silica gel(AcOEt/Hexane: 30/70) to afford the title compound 288 (280 mg, 0.728mmol, 86% yield). ¹H NMR (300 MHz, CDCl₃) δ (ppm): 8.05 (d, J=7.5 Hz,2H), 7.45 (d, J=7.5 Hz, 2H), 6.18-5.95 (m, 4H), 4.38 (q, J=7.0 Hz, 2H),3.88 (s, 6H), 3.84 (s, 3H), 1.39 (t, J=7.0 Hz).

Step 3:N-(2-Amino-phenyl)4-[5-(3,4,5-trimethoxy-phenyl)-2,5-dihydro-furan-2-yl]-benzamide(289)

Following a procedure analogous to that described in Example 1, step 4,5, but substituting 288 for 6, the title compound 289 was obtained in48% yield. ¹H NMR (DMSO) δ (ppm): 8.00 (s, 1H), 7.91 (d, J=7.9 Hz, 2H),7.48 (d, J=7.9 Hz, 2H), 7.33 (d, J=7.5 Hz, 1H), 7.09 (t, J=7.5 Hz, 1H),6.92-6.82 (m, 2H), 6.61 (s, 2H), 6.14-5.99 (m, 4H), 3.89 (s, 6H), 3.84(s, 3H).

Example 169

Step 1:N-(2-Amino-phenyl)4-[5-(3,4,5-trimethoxy-phenyl)-tetrahydro-furan-2-yl]-benzamide.(290)

To a degazed solution of 289 (43 mg, 0.096 mmol) in AcOEt (4 mL) wasadded PtO₂ (3 mg, 0.01 mmol) and the reaction mixture was stirred atroom temperature under a 1 atm pressure of H₂ for 16 h. The reactionflask was purged with N₂ then the reaction mixture was filtered throughcelite, rinsed with MeOH and concentrated. The crude residue waspurified three times by flash chromatography on silica gel (MeOH/DCM:2/98, AcOEt/DCM: 30/70 and AcOEt/CHCl₃: 30/70) to afford the titlecompound 290 (10 mg, 0.22 mmol, 23% yield).¹H NMR (CDCl₃) δ (ppm): 8.10(s, 1H), 7.91 (d, J=8.0 Hz, 2H), 7.50 (d, J=8.0 Hz, 2H), 7.34 (d, J=7.5Hz, 1H), 7.10 (t, J=7.5 Hz, 1H), 6.96-6.85 (m, 2H), 6.64 (s, 2H), 5.33(t, J=7.0 Hz, 1H), 5.21 (t, J=7.0 Hz, 1H), 3.89 (s, 6H) 3.85 (s, 3H),2.59-2.40 (m, 2H), 2.09-1.88 (m, 2H).

Example 169

Step 1: [2-(4-Vinyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester(291)

Following a procedure analogous to that described in Example 143, step2, but substituting 184 for 221, the title compound 291 was obtained in90% yield as a dark yellow oil. ¹H NMR: (300 MHz, CDCl₃) δ (ppm): 9.18(s, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.77 (d, J=7.77 (d, J=7.5 Hz, 7.49 (d,J=8.5 Hz, 2H), 7.30-7.10 (m, 3H), 6.89 (s, 1H), 6.77 (dd, J=17.4, 11.0Hz, 1H), 5.87 (d, J=17.4 Hz, 1H), 5.39 (d, J=11.0 Hz, 1H), 1.52 (s, 9H).

Step 2: [2-(4-Oxiranyl-benzoylamino)-phenyl]-carbamic acid tert-butylester (292)

To a solution of 291 (4.1 g, 12.1 mmol) in dry CHCl₃ (60 mL) was addedm-CPBA 70% (3.6 g, 14.5 mmol). The reaction mixture was stirred at roomtemperature for 5 h then additional m-CPBA (0.6 g, 2.4 mmol) was addedand the stirring continued for 1 h. A further amount of m-CPBA (0.6 g,2.4 mmol) was added and the reaction mixture was stirred for 16 h.Chloroform and a 10% solution of NaHCO₃ were added and the phases wereseparated. The organic layer was washed with water and brine, dried overanhydrous Na₂SO₄, filtered and concentrated. The crude residue was thenpurified by flash chromatography on silica gel (AcOEt/Hexane: 1/3) toafford the title compound 292 (2.86 g, 8.07 mmol, 66% yield). ¹H NMR(300 MHz, CDCl₃) δ (ppm): 9.20 (s, 1H), 7.95 (d,J=8.1 Hz, 2H), 7.86-7.75(m, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.26-7.10 (m, 3H), 6.84-6.70 (m, 1H),3.93 (t, J=3.0 Hz, 1H), 3.20 (t, J=5.0 Hz, 1H), 2.80 (dd, J=5.0, 3.0 Hz,1H), 1.52 (s, 9H).

Step 3:(2-{4-[1-Hydroxy-2-(3,4,5-trimethoxy-phenylamino)-ethyl]-benzoylamino}-phenyl)-carbamicacid tert-butyl ester (295) and(2-{4-[2-Hydroxy-1-(3,4,5-trimethoxy-phenylamino)-ethyl]-benzoylamino}-phenyl)-carbamicacid tert-butyl ester (293)

To a stirred solution of CoCl₂ (8 mg, 0.06 mmol) in dry acetonitrile (10mL) was added 292 (1 g, 2.8 mmol) followed by 3,4,5-trimethoxyaniline(516 mg, 2.8 mmol) and the reaction mixture was allowed to react for 16h at room temperature then it was heated at 60° C. for 5 h. The reactionmixture was partitioned between AcOEt and water and the phases wereseparated. The organic layer was washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated. The crude residue was purified byflash chromatography on silica gel (AcOEt/Hexane: 1/1) to affordcompounds 293 and 295 (combined: 1.07 g, 1.99 mmol, 71% yield, ratio292/295=5/1) which can be separated by flash chromatography on silicagel (AcOEt/Hexane: 1/1). ¹H NMR (300 MHz, CDCl₃) δ (ppm): Compound 292:9.21 (s, 1H), 7.92 (d, J=8.1 Hz, 2H), 7.73 (d, J=6.6 Hz, 1H), 7.46 (d,J=8.1 Hz, 2H), 7.28-7.10 (m, 3H), 6.90 (s, 1H), 5.83 (s, 2H), 4.54-4.44(m, 1H), 3.93 (dd, J=8.1, 3.9 Hz, 1H), 3.84-3.72 (m, 1H), 3.71 (s, 3H),3.66 (s, 6H), 1.47 (s, 9H). Compound 295: 9.22 (s, 1H), 7.91 (d, J=8.1Hz, 2H), 7.77 (d, J=7.2 Hz, 1H), 7.46 (d, J=8.1 Hz, 2H), 7.30-7.21 (m,3H), 6.88 (s, 1H), 6.15 (s, 2H), 5.16-5.06 (m, 1H), 3.81 (s, 6H), 3.78(s, 3H), 3.50-3.25 (m, 2H), 1.51 (s, 9H).

Step 4:N-(2-Amino-phenyl)-4-[2-hydroxy-1-3,4,5-trimethoxy-phenylamino)-ethyl]-benzamide(294)

Following a procedure analogous to that described in Example 42, step 3,but substituting 293 for 46, the title compound 294 was obtained in 50%yield. ¹H NMR (DMSO) δ (ppm): 8.36 (s, 1H), 7.74 (d, J=6.9 Hz, 2H), 7.30(d, J=7.8 Hz, 2H), 7.18 (d, J=6.9 Hz, 1H), 7.00 (t, J=7.2 Hz, 1H), 6.72(m, 2H), 5.69 (s, 2H), 4.34 (m, 1H), 4.02-3.52 (m, 2H), 3.66 (s, 3H),3.57 (s, 6H).

Example 170

Step 1:N-(2-Amino-phenyl)-4-[2-oxo-3(3,4,5-trimethoxy-phenyl)-oxazolidin-4-yl]-benzamide(296)

To a solution of 293 (200 mg, 0.372 mmol) in toluene (5 mL) and THF (1mL) was added 1,1′-carbonyldiimidazole (72 mg, 0.45 mmol) followed byEt₃N (156 μL, 1.12 mmol) and the mixture was stirred at room temperaturefor 5 h then at 90° C. for 48 h. The reaction mixture was diluted withAcOEt, a solution of sat. NH₄Cl was added and the phases were separated.The organic layer was washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated. The crude residue was purified by flashchromatography on silica gel (DCM/AcOEt: 80/20) to afford the desiredcompound (120 mg, 0.21 mmol, 57% yield). ¹H NMR (DMSO) δ (ppm): 9.37 (s,1H), 7.98 (d, J=8.1 Hz, 2H), 7.76 (d, J=7.5 Hz, 1H), 7.41 (d, J=8.1 Hz,2H), 7.25-15 (m, 3H), 6.88 (s, 1H), 6.61 (s, 2H), 5.40 (dd, J=8.7, 6.0Hz, 1H), 4.79 (t, J=8.7 Hz, 1H), 4.19 (dd, J=8.7, 6.0 1H), 3.75 (s, 3H),3.72 (s, 6H), 1.47 (s, 9H).

Following a procedure analogous to that described in Example 42, step 3,but substituting the previous compound for 46, the title compound 296was obtained in 81% yield.). ¹H NMR (DMSO) δ (ppm): 8.03 (s, 1H), 7.91(d, J=8.1 Hz, 2H), 7.41 (d, J=8.1 hz, 2H), 7.30 (d, J=7.5 Hz, 1H), 7.07(t, J=7.5 Hz, 1H), 6.82 (d, J=7.5 Hz, 2H), 6.61 (s, 2H) 5.40 (dd, J=8.7,6.0 Hz, 1H), 4.78 (t, J=8.7 Hz, 1H), 4.18 (dd, J=8.7, 6.0 Hz, 1H), 3.75(s, 3H), 3.71 (s, 6H).

Example 171

Step 1:N-(2-Amino-phenyl)-4-[2-oxo-3-(3,4,5-trimethoxy-phenyl)-oxazolidin-5-yl]-benzamide(297)

To a solution of 295 (130 mg, 0.242 mmol) in DCM (2 mL) was added1,1′-carbonyldiimidazole (47 mg, 0.29 mmol) and the mixture was stirredat room temperature for 16 h. DCM was removed under reduced pressure,AcOEt and a solution of sat. NH₄Cl were added and the phases wereseparated. The organic layer was washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated. The crude residue was purified byflash chromatography on silica gel (Hexane/AcOEt: 30/70) to afford thedesired compound (80 mg, 0.14 mmol, 58% yield). ¹H NMR (DMSO) δ (ppm):9.39 (s, 1H), 8.04 (d, J=8.1 Hz, 2H), 7.84 (d, J=7.5 Hz, 1H), 7.52 (d,J=8.1 Hz, 2H), 7.26-7.12 (m, 3H), 6.86-6.74 (m, 3H), 5.70 (t, J=8.4 Hz,1H), 4.24 (t, J=8.7 Hz, 1H), 3.97-3.87 (m, 1H), 3.87 (s, 6H), 3.82 (s,3H), 1.52 (s, 9H).

Following a procedure analogous to that described in Example 42, step 3,but substituting the previous compound for 46, the title compound 297was obtained in 94% yield.). ¹H NMR (DMSO) δ (ppm): 8.38 (s, 1H), 7.97(d, J=7.5 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.35 (d, J=7.0 Hz, 1H), 7.08(t, J=7.0 Hz, 1H), 6.97-6.87 (m, 2H), 6.79 (s, 2H), 5.66 (t, J=8.1, 1H),4.41 (t, J=9.0 Hz, 1H), 3.91 (t, J=7.8 Hz, 1H), 3.86 (s, 6H), 3.82 (s,3H).

Example 172

Step 1: {2-[4-(1-Azido-2-hydroxy-ethyl)-benzoylamino]-phenyl}-carbamicacid tert-butyl ester (298) and{2-[4-(2-Azido-1-hydroxy-ethyl)-benzoylamino]-phenyl}-carbamic acidtert-butyl ester (302)

To a solution of 292 (210 mg, 0.59 mmol) in acetonitrile (9 mL) andwater (1 mL) was added CeCl₃ heptahydrate (110 mg, 0.296 mmol) followedby NaN₃ (42 mg, 0.65 mmol). The reaction mixture was refluxed for 3 hthen acetonitrile was removed under reduced pressure. The residue wasdiluted with DCM, washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated. Purification by flash chromatography onsilica gel (AcOEt/Hexane: 1/1) afforded a 1:1 mixture of title compounds298 and 302 (combined: 187 mg, 0.47 mmol, 80% yield) which wereseparated by flash chromatography on silica gel (AcOEt/Hexane: 2/5).Compound 298: ¹H NMR: (300 MHz, CDCl₃/CD₃OD) δ (ppm): 7.95 (d, J=8.1 Hz,2H), 7.70-7.63 (m, 1H), 7.43 (d, J=8.1 Hz, 2H), 7.36-7.29 (m, 1H),7.24-7.14 (m, 2H), 4.69 (dd, J=7.5, 4.8 Hz, 1H), 3.80-3.65 (m, 2H), 1.49(s, 9H). Compound 302: ¹H NMR: (300 MHz, CDCl₃) δ (ppm): 9.28 (s, 1H),7.86 (d, J=8.4 Hz, 2H), 7.71 (d, J=7.5 Hz, 1H), 7.38 (d, J=8.4 Hz, 2H),7.25-7.08 (m, 3H), 7.01 (s, 1H), 4.87 (dd, J=6.9, 5.1 Hz, 1H), 3.47-3.38(m, 2H), 3.32-3.21 (bs, 1H), 1.50 (s, 9H).

Step 2: {2-[4-(1-Amino-2-hydroxy-ethyl)-benzoylamino]-phenyl}-carbamicacid tert-butyl ester (299)

To a solution of 298 (156 mg, 0.39 mmol) in MeOH (2 mL) was added Pd/C10% (20 mg, 0.02 mmol). The reaction mixture was stirred under a 1 atmpressure of H₂ at room temperature for 16 h then it was purged with N₂.The palladium was removed by filtration through celite and the MeOH wasevaporated under reduced pressure to afford the title compound 299 (88mg, 0.24 mmol, 60% yield), which was used without purification. ¹H NMR(300 MHz, CDCl₃) δ (ppm): 9.24 (s, 1H), 7.90 (d, J=7.8 Hz, 2H), 7.71 (d,J=6.6 Hz, 1H), 7.40 (d, J=7.8 Hz, 2H), 7.31-7.10 (m, 3H), 7.06-6.94 (m,1H), 4.12 (dd, J=7.5, 4.5 Hz, 1H), 3.74 (dd, J=7.8, 5.4 Hz, 1H),3.64-3.51 (m, 1H), 2.64 (s, 3H), 1.49 (s, 9H).

Step 3:(2-{4-[(3,4-Dimethoxy-benzoylamino)-2-hydroxy-ethyl]-benzoylamino}-phenyl)-carbamicacid tert-butyl ester (300)

To a stirred solution of 299 (88 mg, 0.24 mmol) in dry DCM (2 mL) at−20° C. was added 3,4-dimethoxybenzoyl chloride (50 mg, 0.25 mmol)followed by Et₃N (37 μL, 0.26 mmol). The reaction mixture was allowed towarm up to room temperature then was stirred for 48 h. A solution ofsat. NH₄Cl was added, followed by DCM and the phases were separated. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated. The crude residue was purified by flashchromatography on silica gel (MeOH/DCM: 4/96) to afford title compound300 (91 mg, 0.17 mmol, 71% yield). ¹H NMR (300 MHz, CDCl₃) δ (ppm): 9.29(s, 1H), 7.81 (d, J=8.1 Hz, 2H), 7.65-7.58 (m, 1H), 7.46 (m, 7H), 6.80(d, J=8.1 Hz, 1H), 5.20-5.10 (m, 1H), 3.95-3.78 (m, 2H), 3.88 (s, 3H)3.84 (s, 3H), 1.47 (s, 9H).

Step 4:N-(2-Amino-phenyl)-4-[2-(3,4-dimethoxy-phenyl)-4,5-dihydro-oxazol-4-yl]-benzamide(301)

To a solution of 300 (91 mg, 0.17 mmol) in dry THF (2 mL) was added theBurgess reagent (44 mg, 0.19 mmol) and the mixture was stirred at 70° C.for 2 h. The reaction mixture was partitioned between AcOEt and waterand the phases were separated. The organic layer was washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated. The cruderesidue was purified by flash chromatography on silica gel (MeOH/DCM:3/97) to afford the Boc-protected intermediate (75 mg, 0.14 mmol, 85%yield). ¹H NMR (CDCl₃) δ (ppm): 9.31 (s, 1H), 7.94 (d, J=8.4 Hz, 2H),7.72 (d, J=7.5 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.61 (s, 1H), 7.39 (d,J=8.1 Hz, 2H), 7.27 (d, J=6.0 Hz, 1H), 7.23-7.08 (m, 3H), 6.93 (d, J=8.7Hz, 1H), 5.43 (t, J=9.0 Hz, 1H), 4.84 (t, J=9.3 Hz, 1H), 4.26 (t, J=8.4Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 1.50 (s, 9H).

Following a procedure analogous to that described in Example 42, step 3,but substituting the previous compound for 46, the title compound 301was obtained in 82%. ¹H NMR (CDCl₃) δ (ppm): 8.01 (s, 1H), 7.89 (d,J=7.9 Hz, 2H), 7.65 (dd, J=8.4, 1.5 Hz, 1H), 7.60 (d, J=1.5 Hz, 1H),7.41 (d, J=7.9 Hz, 2H), 7.32 (d, J=7.9 Hz, 1H), 7.08 (t, J=6.6 Hz, 1H),6.92 (d, J=8.4 Hz, 1H), 6.84 (d, J=7.9 Hz, 2H), 5.43 (dd, J=9.7, 8.4 Hz,1H), 4.83 (dd, J =9.7, 8.4 Hz, 1H), 4.25 (t, J=8.1 Hz, 1H), 3.94 (s,3H), 3.93 (s, 3H).

Example 173

Step 1: {2-[4-(2-Amino-1-hydroxy-ethyl)-benzoylamino]-phenyl}-carbamicacid tert-butyl ester (303)

The title compound 303 was obtained in 94% yield from 302 following thesame procedure as in Example 172, step 2. The compound 303 was useddirectly for next step without purification.

Step 2:2-{4-[2-(3,4-Dimethoxy-benzoylamino)-1-hydroxy-ethyl]-benzoylamino}-phenyl)-carbamicacid tert-butyl ester (304)

The title compound 304 was obtained in 40% yield from 303 and3,4-dimethoxybenzoyl chloride following the same procedure as in Example172, step 3. ¹H NMR (CDCl₃) δ (ppm): 9.31 (s, 1H), 7.78 (d, J=8.1 Hz,2H), 7.68 (d, J=6.9 Hz, 1H), 7.38 (d, J=1.8 Hz, 1H), 7.33 (d, J=8.1 Hz),7.30-7.06 (m, 4H), 7.00-6.93 (m, 1H), 6.79 (d, J=8.4 Hz, 1H),4.89-4.89-4.82 (m, 1H), 3.88 (s 3H), 3.86 (s, 3H), 3.85-3.73 (m, 1H),3.44-3.32 (m, 1H), 1.46 (s, 9H).

Step 3:N-(2-Amino-phenyl)-4-[2-(3,4dimethoxy-phenyl)-4,5-dihydro-oxazol-5-yl]-benzamide(305)

Following a procedure analogous to that described in Example 172, step4, 5, but substituting 304 for 300, the title compound 305 was obtainedin 63%. ¹H NMR (CDCl₃) δ (ppm): 8.02 (s, 1H), 7.93 (d, J=8.1 Hz, 2H),7.63 (dd, J=8.4, 1.8 Hz, 1H), 7.60 (s, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.33(d, J=7.5 Hz, 1H), 7.09 (t, J=7.5 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 6.85(d, J=8.1 Hz, 2H), 5.74 (dd, J=10.0, 7.8 Hz, 1H), 4.51 (dd, J=14.5, 10.0Hz, 1H), 4.00-3.90 (m, 7H).

Example 178

Step 1: [2-(4-formyl-benzoylamino)-phenyl]-carbamic acid tert-butylester (315)

To a suspension of 4-carboxybenzaldehyde (6 g, 40 mmol) indichloromethane (10 mL) was added thionyl chloride (4.1 mL, 56 mmol, 1.4eq), followed by DMF (1 mL) dropwise. The mixture was refluxed for 4hours and excess of thionyl chloride and DMF were removed under reducedpressure. To a solution of (2-aminophenyl)-carbamic acid tert-butylester (8.32 g, 40 mmol, 1 eq) in dichloromethane (80 mL), stirred at 0°C., was added a suspension of 4-formyl benzoyl chloride indichloromethane (20 mL), followed by diisopropyl ethylamine (3.61 mL, 20mmol, 1 eq). The mixture was stirred for 30 minutes at 0° C. then atroom temperature for 30 minutes. The crude residue was diluted withdichloromethane (300 mL) and washed with water. The combined organiclayers were dried (MgSO₄), filtered and concentrated under vacuo. Thecrude residue was purified by column chromatography on silica gel(elution 20% ethyl acetate in hexane) to give 6.1 g (45% yield) ofanilide 315. ¹H NMR (CDCl₃): δ 10.18 (s, 1H), 9.64 (brs, 1H), 8.20 (d,J=7.9 Hz, 2H), 8.06 (d, J=7.9 Hz, 2H), 7.96 (d, J=7.9 Hz, 1H), 7.28-7.38(m, 1H), 7.24 (d, J=4.4 Hz, 1H), 6.84 (s, 1H), 6.81 (d, J=8.8 Hz, 1H),1.58 (s, 9H).

Step 2:(2-{4-[(3,4-Dimethoxyphenylamino)-Methyl]-Benzoylamino}-Phenyl)-CarbamicAcid Tert-Butyl Ester (316)

Following a procedure analogous to that described in Example 144, step3, but substituting the previous compound for 226, the title compound316 was obtained in quantitative yield. ¹H NMR (CDCl₃): δ 9.21 (brs,1H), 8.01 (d, J=7.9 Hz, 2H), 7.86 (d, J=7.0 Hz, 1H), 7.55 (d, J=8.3 Hz,2H), 7.20-7.34 (m, 3H), 6.89 (brs, 1H), 6.81 (d, J=8.8 Hz, 1H), 6.37 (d,J=2.2 Hz, 1H), 6.23 (dd, J=2.6, 8.3 Hz, 1H), 4.45 (s, 2H), 3.89 (s, 3H),3.88 (s, 3H), 1.58 (s, 9H).

Step 3:N-(2-Aminophenyl)-4-[1-(3.4-dimethoxyphenyl)-3-(4-methylsulfanylphenyl)-ureidomethyl]-benzamide317

To a solution of anilide 316 (500 mg, 1.047 mmol) in chloroform/THF(1:1, 10 mL) was added isocyanate (169 μL, 1.205 mmol, 1.15 eq). Themixture was stirred overnight at room temperature under nitrogen and thecrude residue was concentrated and purified by column chromatography onsilica gel (elution 40% ethyl acetate in hexane) to give 606 mg (90%yield) of the desired compound. ¹H NMR (CDCl₃): δ 9.25 (s, 1H), 7.96 (d,J=8.3 Hz, 2H), 7.85 (d, J=7.0 Hz, 1H), 7.44 (d, J=8.3 Hz, 2H), 7.20-7.36(m, 6H), 6.93 (d, J=3.5 Hz, 1H), 6.90 (s, 1H), 6.75 (dd, J=2.2, 8.3 Hz,1H), 6.68 (dd, J=2.6 Hz, 1H), 6.33 (s, 1H), 5.0 (s, 2H), 3.97 (s, 1H),3.85 (s, 3H), 2.51 (s, 3H), 1.57 (s, 9H).

Following a procedure analogous to that described in Example 42, step 3,but substituting the previous compound for 46, the title compound 317was obtained in 85% yield. ¹H NMR (DMSO-d₆): δ 10.14 (brs, 1H), 7.99 (d,J=7.9 Hz, 2H), 7.93 (s, 1H), 7.49 (d, J=8.35 Hz, 4H), 7.39 (d, J=7.5 Hz,1H), 7.10-7.30 (2m, 5H), 6.97 (dd, J=2.2, 8.35 Hz, 1H), 6.77 (dd, J=2.2,8.35 Hz, 1H), 5.02 (s, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 2.48 (s, 3H).

Example 179

Step 1: N-(2-Amino-phenyl)-6-chloro-nicotinamide (318)

Following the procedure described in Example 42, step 2, the titlecompound 318 was obtained in 80% yield. LRMS=calc:246.69, found:247.7.

Step 2: N-(2-Amino-phenyl)-6-(quinolin-2-ylsulfanyl)-nicotinamide (319)

Following the procedure described in Example 45, step 1 but substituting318 for 3,4,5-trimethoxybenzylamine, the tite compound 319 was obtainedin 20% yield. ¹H NMR: (CD₃₀OD-d6) δ (ppm): 9.08 (d, J=1.9 Hz, 1H),8.35-8.25 (m, 2H), 7.99-7.56 (m, 7H), 7.23 (dd, J=1.2, 7.9 Hz, 1H), 7.12(dd J=1.4, 7.9, 14.0 Hz, 1H), 6.93 (dd, J=1.2, 8.0Hz, 1H), 6.79 (ddd,J=1.4, 7.7, 13.7 Hz, 1H).

Step 1: 4-[(4-Morpholin-4-yl-phenylamino)-methyl]-benzoic acid (402a)

A suspension of 4-formylbenzoic acid (2.53g; 16.8 mmol; 1 eq),4-morpholinoaniline (3g; 16.8 mmol; 1 eq) and BU₂SnCl₂ (510 mg; 1.68mmol; 0.1 eq) in dry THF (20 ml) was treated with PhSiH₃ (3.31 ml; 16.8mmol; 1 eq) at room temperature for 12 h. The reaction was filtered andthe solid product was washed with MeOH. The yield of the reaction was5.25g (99%). LRMS: calc 312.37; found: 313.2.

Step 2:N-(2-Amino-phenyl)-4-[(4-morpholin-4-yl-phenylamino)-methyl]-benzamide(402)

To a solution of acid 402a (2.61g; 8.36 mmol; 1 eq),1,2-phenylenediamine (903 mg; 8.36 mmol; 1 eq) and BOP (3.70 g; 8.36mmol; 1 eq) in dry DMF (20 ml) was added Et₃N (4.64 ml; 33.4 mmol; 4eq). After stirring overnight most of the DMF was removed under reducedpressure and chromatographed (Hex:EtAcO: 1:2/EtAcO). The crystal 402 wasobtained in 70% (2.35 g). ¹H-NMR (300.07 MHz; DMSO-d6) δ (ppm): 9.65 (s,1H), 7.97 (d, J=7.9, 2H), 7.53 (d, J=7.9, 2H), 7.22 (d, J=7.5, 1H), 7.03(dd, J=7.0, 7.5, 1H), 6.83 (d, J=7.9, 1H), 6.77 (d, J=8.8, 2H), 6.65(dd, J=7.5, 7.0,1H), 6.57 (d, J=8.8, 2H), 4.93 (bs, 2H), 4.36 (d, J=5.7,2H), 3.75 (m, 4H), 2.93 (m, 4H). LRMS: calc 402.49; found: 403.4.

Example 283a

Step 1. 4-[(3,4-Dimethoxyphenylamino)-methyl]-benzoic acid (424a)

In a 50 ml flask, a mixture of 4-aminoveratrole (1.53 g, 10 mmol),4-formyl-benzoic acid (1.50 g, 10 mmol), dibutyltin dichloride (304 mg,1 mmol), phenylsilane (2.47 ml, 20 mmol) in anhydrous THF (10 mL) andDMA (10 ml) was stirred overnight. at room temperature. After solventsremoval, the crude residue was dissolved in ethyl acetate (100 ml) andthen washed with saturated aqueous solution of NaHCO₃ (50 ml×3). Thecombined aqueous layers were acidified with 6% of NaHSO₄ to pH=4. Theresulting white suspension was filtrated and then the filter cake waswashed with water (5 ml×3). The cake was dried over freeze dryer toafford acid (1.92 g, 67%) white solid product. LRMS=288 (MH)⁺.

Step 2.N-(2-Aminophenyl)-4-[(3,4-dimethoxyphenylamino)-methyl]-benzamide (424b)

In a 150 ml flask, a mixture of acid (1.92 g, 6.69 mmol),benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(BOP, 3.26 g, 7.37 mmol), triethylamine (1.87 ml, 13.4 mmol),o-phenylenediamine (1.30 g, 12.02 mmol) in methylenechloride (67 ml) wasstirred at rt for 2 h. After solvents removal, the crude residue wasdissolved in EtOAc (100 ml) and then washed with NaHCO₃ saturatedsolution and brine 50 ml. The combined organic layers were dried overNa₂SO₄ and the filtrate was concentrated to dryness. The crude materialwas submitted to a chromatographic purification (column silica, 55%-70%EtOAc in 1% Et₃N of hexanes) and then the all interested fractions wereconcentrated to dryness. The residue was suspended in minimum quantitiesof ethyl acetate and then filtered to afford final product (1.49 g,59%). ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.65 (s, 1H), 7.98 (d, J=7.9Hz, 2H), 7.54 (d, J=7.9 Hz, 2H), 7.22 (d, J=7.9 Hz, 1H), 7.02 (dd,J=7.9, 7.9 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H), 6.72 (d, J=8.79 Hz, 1H),6.45 (dd, J=7.5, 7.5 Hz, 1H), 6.39 (d, J=2.2 Hz, 1H), 6.01-6.08 (m, 2H),4.94 (s, 2H, NH₂), 4.36 (d, J=6.16 Hz, 2H), 3.72 (s, 3H), 3.65 (s, 3H).

Example 283b

Step 1:N-(4-Aminothiophen-3:yl)-4-[(3,4-dimethoxyphenylamino)-methyl]-benzamide:

Acid 424a (1040 mg; 3.62 mmol); 3,4-diaminothiophene dihydrochloride(1017 mg; 5.44 mmol; 1.50 eq.) and BOP (1770 mg; 4.0 mmol; 1.1 eq.) weresuspended in MeCN, treated with triethylamine (4 mL; 29 mmol) andstirred for 18 h at room temperature; concentrated and purified bychromatographic column on silica gel (elution 50% EtOAc in DCM) torender 527 mg (1.37 mmol; 38% yield) of compound 424c which was 90%pure. 1H-NMR (300.07 MHz; DMSO-d6) δ (ppm): 8.56 (s, 1H), 7.78 (d, J=7.9Hz, 2H), 7.43 (d, J=3.5 Hz, 1H), 7.38 (d, J=7.9 Hz, 2H) 6.73 (d, J=8.8Hz, 1H), 6.33 (d, J=3.5 Hz, 1H), 6.58 (d, J=2.6 Hz, 1H), 6.13 (dd,J=2.6, 8.3 Hz, 1H), 4.33 (s, 2H), 3.80 (s, 3H), 3.78 (s, 3H). LRMS:calc: 383.4642; found: 384.2 (M+H); 406.2 (M+Na) and 192.6 (M+2H)/2.

Step 1: Methyl-(5-nitrobenzothiazol-2-yl)-amine (456a)

A mixture of 2-fluoro-5-nitroaniline (861 mg; 5.52 mmol; 1.02 eq); Im₂CS(960.3 mg; 5.39 mmol) and dry K₂CO₃ (1.45g) was suspended in dry DME (10mL) and stirred under nitrogen for 90 min at room temperature. Theyellow suspension was made fluid by diluting with DME (10 mL) followedby addition of 40% MeNH₂ in water (4.0 mL; 46.5 mmol; 8.6 eq). Thesystem was heated up to 65 C. and stirred at this temperature for 3.5 h,cooled down, diluted with ethyl acetate and washed with saturated NaCl(×2). After conventional work-up procedures, the dark crude mixture waspurified through chromatographic column on silica gel (elution 50% EtOAcin hexane, then 5% MeOH in DCM), to afford 836.8 mg (4.0 mmol; 72%yield) of compound 456a.

Step 2: N-Methyl-benzothiazole-2,5-diamine (456b)

A mixture of nitro compound 456a (593 mg; 2.83 mmol); SnCl₂ (4.02 g;20.8 mmol; 7.35 eq) and NH₄OAc (4.5g) was suspended inTHF:MeOH:H₂O=1:1:1 (60 mL) and stirred at 70° C. for 2 h, cooled down,diluted with ethyl acetate and successively washed with saturated NaHCO₃and brine; dried (MgSO₄) filtered and concentrated. The residue (443 mg;2.43 mmol; 87%) showed consistent spectrum and suitable purity degreefor synthetic purposes, therefore was submitted to the next step withoutfurther purification.

Step 3: 4-[(2-Methylaminobenzothiazol-5-Ylamino)-Methyl]-Benzoic Acid(456c)

A solution of aniline 456b (509 mg; 2.8 mmol); 4-formylbenzoic acid (426mg; 2.8 mmol) and Bu₂SnCl₂ (198 mg; 0.65 mmol; 23% mol) in DME (14 mL)was stirred at room temperature for 3 min and treated with neat PhSiH₃(0.6 mL; 4.7 mmol; 1.7 mmol) and allowed to react for 18 h. Afterquenching the excess of silane with MeOH, the mixture was concentratedand purified by chromatographic column on silica gel (elution 5% MeOH inDCM) to give 729 mg (2.54 mmol; 91% yield) of acid 456c.

Step 4:N-(2-Aminophenyl)-4-[(2-methylaminobenzothiazol-5-ylamino)-methyl]-benzamide(456)

A mixture of acid 456c (729 mg; 2.54 mmol), 1,2-phenylenediamine (376mg; 3.47 mmol; 1.36 eq) and BOP (1.43 g; 3.23 mmol; 1.27 eq) wasdissolved in acetonitrile (15 mL), treated with triethylamine (3mL) andstirred overnight. The reaction mixture was quenched with methanol,concentrated and purified by chromatographic column on silica gel (40%EtOAc in DCM) and the obtained material crystallized from DCM to give358 mg (0.88 mmol; 35% yield) of pure compound 456. ¹H-NMR (300 MHz;DMSO-d6) δ (ppm): 9.57 (s, 1H), 7.92 (d, J=7.9 Hz, 2H), 7.66 (d, J=4.8Hz, 1H), 7.48 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 1H), 7.15 (d, J=7.9Hz, 1H), 6.95 (t, J=7.5 Hz, 1H), 6.76 4.87 (bs, 2H), 6.58 (t, J=7.5 Hz,1H), 6.54 (d, J=1.8 Hz, 1H), 6.13 (dd, J=1.8, 8.3 Hz, 1H), 6.27 (t,J=5.7 Hz, 1H), 4.87 (bs, 2H), 4.36 (d, J=5.7 Hz, 2H), 2.85 (d, J=4.8 Hz,3H). LRMS: calc: 403.5008, found: 404.2 (M+NH) and 202.6 (M+2H)/2.

Example 235

Step 1:Methyl-4-(5-methoxy-1H-benzimidazol-2-yl-sulfanylmethyl)-benzoate (376a)

To a solution 5-methoxy-2-thiobenzimidazole (2.00 g, 11.1 mmol of inanhydrous DMF (40 ml) was added methy-4-bromomethyl)-benzoate (2.54 g,11.1 mmol). The reaction mixture was stirred 16 h at room temperature.The DMF was evaporated and the residue was triturated in ethyl acetateduring 30 min and then filtered and dried. The desired compound wasisolated as the HBr salt: 98% yield, (4.44 g). ¹H NMR: (DMSO) δ (ppm):7.90 (d, J=8.8 Hz, 2H), 7.56-7.52 (m, 3H), 7.09 (d, J=2.2 Hz, 1H), 7.01(dd, J=8.8, 2.2 Hz, 1H), 4.73 (s, 2H), 3.82 (s, 6H). MS: (calc.) 328.1,(obt.), 329.2 (MH)+.

Step 2: 4-(5-Methoxy-1H-benzimidazol-2-yl-sulfanylmethyl)-benzoic acid(376b)

A solution of LiOH.H20 (1.02 g, 24.4 mmol) in water (15 ml) was added toa suspension of 376a (3.99 g, 9.75 mmol of in THF (10 ml). The reactionmixture was stirred 16 h at room temperature. The reaction mixture wasacidified with a solution of HCl 1 M to pH 4. The desired product wastriturated 20 min. at 0° C. and then filtered and dried. Compound 376bwas obtained as a white powder (100% yield, 3.05 g). ¹H NMR: (DMSO) δ(ppm): 12.85 (bs, 1H), 7.86 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H),7.35 (d, J=8.1 Hz, 1H), 6.97 (d, J=2.2 Hz, 1H), 6.76 (dd, J=8.8, 2.2 Hz,1H), 4.60 (s, 2H), 3.82 (s, 3H). MS: (calc.) 314.1, (obt.), 315.1 (MH)+.

Step 3:N-(2-Amino-phenyl)-4-5-methoxy-1H-benzimidazol-2-yl-sulfanylmethyl)-benzamide(376)

Following the procedure described in Example 1 step 5 but substituting445-methoxy-1H-benzimidazol-2-yl-sulfanylmethyl)-benzoic acid 2 for 7the title compound 376 was obtained as a white powder.: 36% yield (933mg). ¹H NMR: (DMSO) δ (ppm): 12.42 (bs, 1H), 9.57 (bs, 1H), 7.89 (d,J=8.1 Hz, 2H), 7.55 (d, J=8.1 Hz, 2H), 7.34 (d, J=8.8 Hz, 1H), 7.14 (d,J=7.32 Hz, 1H), 6.98-6.93 (m, 2H), 6.77-6.55 (m, 2H), 6.58 (dd, J=7.3,7.3 Hz, 1H), 4.87 (s, 2H), 3.77 (s, 3H). MS: (calc.) 404.1, (obt.),405.4 (MH)+.

Examples 180-328

Examples 180 to 327 (compounds 320-468) were prepared using the sameprocedure as described for compound 126 to 319 in Example 85 to 179(scheme 11 to 58).

Examples 329-344

Examples 329 to 344 (compounds 470-485) were prepared using the sameprocedure as described for compound 8 to 224 in Example 1 to 143 (scheme1 to 32).

Example 345

Step 1: Methyl 3-(4-bromo-phenyl)-acrylic ester (486)

To a solution of anhydrous i-Pr₂NH (758 μl, 5.40 mmol) in anhydrous THF(25 ml) stirred at 0° C. under nitrogen, was slowly added a solution ofn-BuLi (2.22 ml, 5.54 mmol, 2.5 M in hexane). After 30 min, LDA wascooled to −78° C. and anhydrous methyl acetate (430

1, 5.40 mmol) was added dropewise. After 30 min, a solution of4-bromobenzaldehyde (500 mg, 2.70 mmol) in anhydrous THF (10 ml) wasslowly added. After 30 min, a solution of2-chloro-4,6-dimethoxy-1,3,5-triazine (569 mg, 3.24 mmol) in anhydrousTHF (15 ml) was added. Then, the temperature was allowed to warm up toroom temperature overnight. A suspension appeared. The reaction mixturewas poured into a saturated aqueous solution of NH₄Cl, and diluted withAcOEt. After separation, the organic layer was successively washed withH₂O and brine, dried over MgSO₄, filtered and concentrated. The crudeproduct was purified by flash chromatography on silica gel(AcOEt/hexane: 10/90) to give the title product 486 (394 mg, 1.9 mmol,61% yield) as a colorless crystalline solid. ¹H NMR (300 MHz, CDCl₃) δ(ppm): 7.63 (d, J=16.2 Hz, 1H), AB system (δ_(A)=7.53, δ_(B)=7.39, J=8.4Hz, 4H), 6.43 (d, J=15.8 Hz, 1H), 3.82 (s, 3H).

Step 2: Methyl 3-[4-(3,4,5-trimethoxy-phenylamino)-phenyl]-acrylic ester(487)

A mixture of Cs₂CO₃ (378 mg, 1.16 mmol), Pd(OAc)₂ (6 mg, 0.025 mmol),(rac)-BINAP (23 mg, 0.037 mmol), was purged with nitrogen for 10 min.486 (200 mg, 0.83 mmol), 3,4,5-trimethoxyaniline (182 mg, 0.99 mmol),and anhydrous toluene (5 ml) were added, respectively. The reactionmixture was heated to 100° C. under nitrogen for 24 h. Then, it wasallowed to cool to room temperature, diluted with AcOEt, andsuccessively washed with a saturated aqueous solution NaHCO₃, H₂O, sat.NH₄Cl, H₂O and brine, dried over anhydrous MgSO₄, filtered andconcentrated. The crude residue was then purified by flashchromatography on silica gel (AcOEt/hexane: 40/60) to afford the titlecompound 487 (280 mg, 0.82 mmol, 98% yield) as a yellow oil. ¹H NMR (300MHz, CDCl₃) δ (ppm): 7.64 (d, J=16.2 Hz, 1H), 7.43 (bd, J=7.9 Hz, 2H),7.12-6.86 (m, 2H), 6.60-6.20 (m, 3H, included at 6.29, d, J=15.8 Hz),3.84 (s, 9H), 3.80 (s, 3H). Step 3:N-(2-Amino-phenyl)-3-[4-(3,4,5-trimethoxy-phenylamino)-phenyl]-acrylamide(488)

The title compound 488 was obtained from 487 in 2 steps following thesame procedure as Example 1, steps 4 and 5. ¹H NMR (300 MHz, DMSO-d₆) δ(ppm): 9.29 (s, 1H), 8.48 (s, 1H), 7.60-7.42 (m, 3H), 7.38 (d, J=7.5 Hz,1H), 7.12 (d, J=8.4 Hz, 2H), 6.94 (t, J=7.5 Hz, 1H), 6.78 (d, J=7.9 Hz,1H), 6.71 (d, J=15.8 Hz, 1H), 6.61 (t, J=7.1 Hz, 1H), 6.47 (s, 2H), 4.97(s, 2H), 3.79 (s, 6H), 3.66 (s, 3H).

Example 346

Step 1: 3-(4-Formyl-3-methoxy-phenyl)-acrylic acid tert-butyl ester 489

Following the procedure described in Example 53, step 1, butsubstituting 4-hydroxy-2-methoxy-benzaldehyde for 84, followed byExample 42, step 2, but substituting the previous compound for 42, thetitle compound 489 was obtained in 29% yield. LRMS=calc: 262, found:263.2 (M+H⁺).

Step 2:3-{3-Methoxy-4-[(3,4,5-trimethoxy-phenylamino)-methyl]-phenyl}-acrylicacid tert-butyl ester 490

Following the procedure described in Example 144, step 3, butsubstituting 489 for 4-formylbenzaldehyde, the title compound 490 wasobtained in 69% yield. LRMS=calc: 429, found: 430.5 (M+H⁺).

Step 3:N-(2-Amino-phenyl)-3-{3-methoxy-4-[(3,4,5-trimethoxy-phenylamino)-methyl]-phenyl}-acrylamide491

Following the procedure described in Example 42, step 3, 4, butsubstituting 490 for 46, the title compound 491 was obtained in 67%yield. ¹H NMR (CDCl₃), δ (ppm): 8.08 (s, 1H), 7.74 (d, J=15.4 Hz, 1H),7.30 (m, 1H), 7.06 (m, 3H); 6.80 (m, 3H), 6.70 (d, J=15.4 Hz, 1H), 5.98(s, 2H), 4.40 (s, 2H); 4.12 (bs, 3H), 3.94 (s, 3H), 3.84 (s, 3H), 3.77(s, 6H).

Example 436

Step 1: Methyl-5-methyl-benzofuran-2-carboxylate (583)

A stirring suspension of 5-methylsalicylaldehyde (1.0 mg, 7.5 mmol),K₂CO₃(1.55 g, 11.0 mmol), and Bu₄NBr (322 mg, 1 mmol) in toluene (30 ml)was treated with dimethylbromomalo-nate (1.06 ml, 8.0 mmol). Thesuspension was heated to reflux with a Dean-Stark trap for 20 h. Thebrown suspension was cooled to 25° C. and concentrated in vacuo. Theresidue was taken in DCM and filtered. The filtrate was washed with H₂O,1N NaOH and brine. The organic layer was dried over magnesium sulfate,filtered and concentrated. The crude residue was purified by columnchromatography (10% ethyl acetate/hexane) to afford the title compound583 (600 mg, 42% yield). LRMS: 190.2 (Calc.); 191.1 (found).

Step 2: Methyl-5-bromomethyl-benzofuran-2-carboxylate (585)

A mixture of 583 (500 mg, 2.63 mmol), N-bromosuccinimide (561 mg, 3.15mmol) and 1,1′-azobis(cyclohexanecarbonitrile) (Vazo) (63 mg, 0.26 mmol)in 15 ml of CCl₄ was heated overnight under reflux. The mixture wascooled to room temperature, quenched by adding water and extracted withDCM. The organic layer was washed with brine and dried over MgSO₄,filtered and concentrated. The crude residue was purified by columnchromatography (30% ethyl acetate/hexane) to afford the title compound585 (680 mg, 96% yield). ¹H NMR: (CDCl₃) δ (ppm): 7.79 (s, 1H),7.70-7.52 (m, 3H), 4.69 (s, 2H), 4.06 (s, 3H), 3.72 (s, 2H). LRMS: 268.2(Calc.); 269.1 (found).

Step 3:Methyl-5-[(3,4-dimethoxy-phenylamino)-methyl]-benzofuran-2-carboxylate(586)

Following the procedure described in Example 47, step 2, butsubstituting 585 for 63, the title compound 586 was obtained in 40%yield. LRMS: 341 (Calc.); 342.3 (found).

Step 4: 5-[(3,4-Dimethoxy-phenylamino)-methyl]-benzofuran-2-carboxylicacid (2-amino-phenyl)-amide (587)

Following the procedure described in Example 1, steps 4,5, butsubstituting 585 for 6, the title compound 587 was obtained in 29%yield. ¹H NMR: (DMSO) δ (ppm): 9.83 (s, 1H), 7.75 (s, 1H), 7.64 (s, 1H),7.62 (d, J=8.0 Hz, 1H), 7.47 (d, J=9.0 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H),6.97 (t, J=7.5 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H), 6.65 (d, J=8.5 Hz, 1H),6.59 (t, J=7.5 Hz, 1H), 6.33 (s, 1H), 6.04 (d, J=8.0 Hz, 1H), 5.92 (d,J=5.5 Hz, 1H), 4.93 (s, 2H), 4.31 (d, J=5.5 Hz, 1H), 2.82 (s, 3H), 2.76(s, 3H). LRMS: 417.46 (Calc.); 418.4 (found).

Example 437

Step 1: Methyl-5-nitro-benzo[b]thiophene-2-carboxylate (584)

A stirring suspension of 5-nitro-2-chloro-benzaldehyde (4.0 g, 21.6mmol) in DMF (40 ml) at 5° C. was treated with K₂CO₃(3.52 g, 25.5 mmol)followed by methylglycolate (1.93 ml, 21.6 mmol). The resulting solutionwas warmed to 25° C. and stirred for 20 h. The solution was then pouredinto 250 ml of ice H₂O and the white precipitate that formed wascollected by filtration. Crystallization from EtOAc afforded fine paleorange needles of 584 (3.54 g, 69%). LRMS: 237.0 (Calc.); 238.1 (found).¹H NMR: (DMSO) δ (ppm): 9.00 (d, J=2.2 Hz, 1H), 8.45 (s, 1H), 8.39-8.30(m, 2H), 3.93 (s, 3H).

Step 2: Methyl-5-amino-benzo[b]thiophene-2-carboxylate (588)

A suspension of 584 (3.52 g, 14.8 mmol) in methanol (100 ml) was treatedwith Fe powder (6.63 g, 118.7 mmol). The resulting suspension was heatedto reflux, and 12M HCl (8.5 ml) was slowly added over 15 min. Theresulting green dark suspension was refluxed for an additional 3 h, thencooled and concentrated. The residue was taken up in EtOAc and washedwith saturated aqueous NaHCO₃, then brine, dried over MgSO₄, filteredand concentrated to afford (2.57 g, 84%). ¹H NMR: (DMSO) δ (ppm): 7.92(s, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.05 (d, J=1.5 Hz, 1H), 6.88 (dd,J=1.8, 8.4 Hz, 1H), 5.27 (s, 2H), 3.85 (s, 3H). LRMS: 207.0 (Calc.);208.1 (found).

Step 3:Methyl-5-(3,4,5-trimethoxy-benzylamino)-benzo[b]thiophene-2-carboxylate(589)

Following the procedure described in Example 144, step 3, butsubstituting 588 for 226, the title compound 589 was obtained in 68%yield. (DMSO) δ (ppm): 7.94 (s, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.02-6.99(m, 2H), 6.73 (s, 2H), 6.41 (t, J=5.7 Hz, 1H), 4.21 (d, J=5.9 Hz, 2H),3.84 (s, 3H), 3.75 (s, 6H), 3.62 (s, 3H). LRMS: 387.1 (Calc.); 388.3(found).

Step 4: 5-(3,4,5-Trimethoxy-benzylamino)-benzo[b]thiophene-2-carboxylicacid (2-amino-phenyl)-amide (590)

Following the procedure described in Example 1, steps 4,5, butsubstituting 589 for 6, the title compound 590 was obtained in % yield¹HNMR: (DMSO) δ (ppm): 7.79 (s, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.00-6.95 (m,2H), 6.74 (s, 2H), 4.32 (s, 2H), 3.80 (s, 6H), 3.73 (s, 3H).

Examples 347-425

Examples 347 to 425 (compounds 492-570) were prepared using the sameprocedure as described for compound 44 to 491 in Example 40 to 346(scheme 3 to 64).

Assay Example 1 Inhibition of Histone Deacetylase Enzymatic Activity

1. Human HDAC-1

HDAC inhibitors were screened against a cloned recombinant human HDAC-1enzyme expressed and purified from a Baculovirus insect cell expressionsystem. For deacetylase assays, 20,000 cpm of the [³H]-metabolicallylabeled acetylated histone substrate (M. Yoshida et al., J. Biol. Chem.265(28): 17174-17179 (1990)) was incubated with 30 μg of the clonedrecombinant hHDAC-1 for 10 minutes at 37° C. The reaction was stopped byadding acetic acid (0.04 M, final concentration) and HCl (250 mM, finalconcentration). The mixture was extracted with ethyl acetate and thereleased [³H]-acetic acid was quantified by scintillation counting. Forinhibition studies, the enzyme was preincubated with compounds at 4° C.for 30 minutes prior to initiation of the enzymatic assay. IC₅₀ valuesfor HDAC enzyme inhibitors were determined by performing dose responsecurves with individual compounds and determining the concentration ofinhibitor producing fifty percent of the maximal inhibition. IC₅₀ valuesfor representative compounds are presented in the third column of Table5.

2. MTT Assay

HCT116 cells (2000/well) were plated into 96-well tissue culture platesone day before compound treatment. Compounds at various concentrationswere added to the cells. The cells were incubated for 72 hours at 37° C.in 5% CO₂ incubator. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, Sigma) was added at a final concentration of 0.5mg/ml and incubated with the cells for 4 hours before one volume ofsolubilization buffer (50% N,N-dimethylformamide, 20% SDS, pH 4.7) wasadded onto the cultured cells. After overnight incubation, solubilizeddye was quantified by calorimetric reading at 570 nM using a referenceat 630 nM using an MR700 plate reader (Dynatech Laboratories Inc.). ODvalues were converted to cell numbers according to a standard growthcurve of the relevant cell line. The concentration which reduces cellnumbers to 50% of that of solvent treated cells is determined as MTTIC₅₀. IC₅₀ values for representative compounds are presented in thefourth column of Table 5.

3. Histone H4 Acetylation in Whole Cells by Immunoblots

T24 human bladder cancer cells growing in culture were incubated withHDAC inhibitors for 16 h. Histones were extracted from the cells afterthe culture period as described by M. Yoshida et al. (J. Biol. Chem.265(28): 17174-17179 (1990)). 20 g of total histone protein was loadedonto SDS/PAGE and transferred to nitrocellulose membranes. Membraneswere probed with polyclonal antibodies specific for acetylated histoneH-4 (Upstate Biotech Inc.), followed by horse radish peroxidaseconjugated secondary antibodies (Sigma). Enhanced Chemiluminescence(ECL) (Amersham) detection was performed using Kodak films (EastmanKodak). Acetylated H-4 signal was quantified by densitometry.Representative data are presented in the fifth column of Table 5. Dataare presented as the concentration effective for reducing the acetylatedH-4 signal by 50% (EC₅₀).

TABLE 5a Inhibition of Histone Deacetylase Human MTT H4Ac HDAC-1(HCT116) (T24) Cpd Structure IC₅₀(μM) IC₅₀(μM) EC₅₀(μM)  8

0.4 0.5 1  9

2 0.7 5 10

2 0.6 1 11

2 0.6 2 12

2 2 5 14

0.3 1 5 15

0.5 0.2 3 16

1 0.4 1 17

0.9 1 2 18

0.8 0.6 3 18b

0.6 5 10 19

0.9 1 1 20

0.5 0.3 1 21

4 4 25 22

3 0.8 1 23

2 0.7 1 24

3 0.6 1 25

0.8 0.3 5 26

0.5 2 na 27

0.4 2 na 28

2 0.5 1 29

2 2 1 30

1 3 1 83

3 5 5 (na = not available; 99 = >25 μM)

TABLE 5b

Human MTT HDAC-1 (HCT116) H4Ac(T24) Ex Cpd Structure IC₅₀(μM) IC₅₀(μM)EC₅₀(μM) 135 204

4 na 5 136 207

0.4 0.6 2 137 210

3 0.9 1 138 212

3 1 1 139 214

3 0.9 1 140 216

0.5 0.4 2 141 218

0.1 0.5 na 142 220

7 6 na 143a 223

11 2 na 143b 224

5 3 na 329 470

2 0.7 3 330 471

0.4 1 3 331 472

3 1 1 332 473

4 3 na 333 474

3 1 1 334 475

0.6 2 na 335 476

2 1 2 336 477

1 0.7 na 337 478

3 0.7 na 338 479

0.4 0.6 na 339 480

0.8 0.5 na 340 481

6 0.7 na 341 482

0.1 0.7 na 342 483

4 na na 343 484

2 0.3 na 344 485

0.4 3 na (na = nonavailable)

TABLE 5c HumanHDAC-1 MTT(HCT116) H4Ac(T24) Cpd Structure IC₅₀(μM)IC₅₀(μM) EC₅₀(μM) 51

22 4 na 55b

3 8 3 59

12 22 na 61b

7 12 na 65

4 37 na 71

10 44 na 72

16 21 na 88

na >39 na 90

10 5 5 91

4 7 5 92

5 2 3 93

3 1 5 94

3 2 5 95

3 2 10 96

4 3 25 97

10 12 na 98

0.4 2 15 99

2 5 10 100

4 3 5 101

3 0.9 5 102

20 6 na 104

10 9 5 105

16 14 na 106

2 2 1 107

15 17 na 108

3 5 5 109

5 8 15 110

3 999 na 111

10 2 99 112

2 5 5 113

0.3 5 114

25 0.5 99 115

15 9 na 116

4 2 5 117

7 3 na 118

11 8 na

TABLE 5d HDAC-1 MTT(HCT116) H4Ac(T24) Ex. Cpd Structure IC50(μM)IC50(μM) EC50(μM) 338 481

22 10 — 339 484

20 12 — 347 492

4 9 10 348 493

4 5 — 349 494

3 4 — 350 495

4 7 — 351 496

8 13 — 352 497

15 6 — 353 498

>25 — — 354 499

>25 2 >25 355 500

23 37 — 356 501

4 10 — 357 502

3 >25 — 358 503

5 >25 — 359 504

5 >25 — 360 505

3 6 — 361 506

15 11 — 362 507

17 10 — 363 508

22 11 — 364 509

17 11 — 365 510

6 5 — 366 511

4 >25 — 367 512

3 3 5 371 516

15 15 — 372 517

6 5 — 373 518

4 2 5 374 519

99 6 — 375 520

5 3 — 376 521

5 2 10 377 522

17 30 — 378 523

8 6 10 379 524

3 2 3 380 525

3 4 5 381 526

2 0.8 1 382 527

4 3 — 383 528

20 32 — 384 529

5 17 — 385 530

8 9 — 386 531

3 2 20 387 532

3 5 — 388 533

5 11 — 389 534

3 5 — 390 535

4 6 — 391 536

18 9 — 392 537

11 2 >25 393 538

4 12 — 394 539

2 10 — 395 540

10 10 — 396 541

4 12 — 397 542

2 5 4 398 543

15 >25 — 399 544

17 45 — 400 545

2 12 — 401 546

3 10 — 402 547

4 8 — 403 548

3 9 — 404 549

4 19 — 405 550

4 15 — 406 551

24 9 — 407 552

4 22 — 408 553

4 12 — 409 554

15 12 — 410 555

14 7 — 411 556

1 0.4 15 412 557

4 6 — 413 558

7 10 — 414 559

4 11 — 415 560

21 6 — 416 561

>25 >25 — 417 562

5 5 — 418 563

24 6 — 419 564

>25 >25 — 420 565

5 17 — 421 566

3 16 — 422 567

13 3 — 423 568

>25 39 — 424 569

18 6 — 425 570

6 0.6 2

TABLE 5e Human HDAC-1 MTT(HCT116) H4Ac(T24) Cpd Structure IC₅₀(μM)IC₅₀(μM) EC₅₀(μM) 87

2 1 5 126

0.3 0.2 1 128

1 0.3 5 131

0.3 0.9 2 139

3 3 5 141

7 10 na 149

1 5 5 152

0.3 11 na 154

0.3 0.4 <1 155

0.4 0.4 1 157

2 0.6 1 158

0.4 0.2 1 164

3 2 3 165

9 4 25 166

2 5 5 167

4 0.5 2 168

3 0.8 2 169

0.3 0.7 1 171

8 3 25 172

0.4 1 3 174

4 0.4 5 175

4 0.5 3 176

5 1 3 177

1 0.4 1

TABLE 5f Human MTT HDAC-1 (HCT116) H4 Ac(T24) Ex Cpd Structure IC₅₀(μM)IC₅₀(μM) EC₅₀(μM) 117 179

1 0.3 1 118 180

3 2 5 119 181

0.5 0.4 1 122 186

2 2 2 123 187

2 5 2 125 189

3 2 5 126 190

3 1 >5 127 192

2 1 3 128 193

4 16 129 194

3 11 130 195

7 9 131 196

4 3 132 198

24 14 133 199

7 9 134 201

11 5 144 228

3 0.3 1 145 231

4 1 3 146 233

0.9 0.3 1 147 236

5 6 148 238

3 6 149 240

1.8 10 150 243

2 0.8 1 151 247

3 0.6 2 152 249

4 1 2 153 252

8 1 2 154 255

2 0.8 1 155 257

0.4 0.4 1 156 259

3 0.3 1 157 262

0.5 0.3 1 158 265

2 2 3 159 266

0.4 0.9 2 160 269

9 4 161 270

4 1 5 162 272

2 0.6 <1 163 275

4 0.9 2 164 277

4 0.3 1 165 281

0.5 0.6 1 166 284

3 5 167 286

5 2 168 289

17 5 169 290

11 3 170 296

20 7 171 297

7 0.4 1 172 301

3 3 173 305

4 2 174 311

0.9 0.7 1 178 317

2 0.3 1 179 319

4 8 180 320

2 1 181 321

0.5 0.3 5 182 322

0.7 0.4 2 183 323

1 0.6 1 184 325

0.3 1 2 185 326

1 1 3 186 327

2 5 3 187 328

17 10 189 330

3 2 1 190 331

4 10 191 332

0.4 1 5 192 333

2 0.1 1 193 334

8 0.2 1 195 336

1 0.4 <1 196 337

3 0.6 1 197 338

2 0.5 3 198 339

4 3 199 340

2 1 1 200 341

4 1 3 201 342

3 0.4 1 202 343

0.5 0.3 1 203 344

0.5 0.2 1 204 345

0.4 0.8 1 205 346

3 0.5 <1 206 347

2 0.6 2 207 348

2 0.3 1 208 349

13 1 3 209 350

2 1 5 211 352

16 9 212 353

3 10 213 354

15 5 214 355

25 10 215 356

5 2 216 357

4 0.4 2 217 358

3 1 2 218 359

2 0.3 1 219 360

5 0.2 1 220 361

2 0.5 1 221 362

2 0.7 1 222 363

1 0.3 3 223 364

4 0.6 224 365

3 0.6 3 225 366

14 10 226 367

6 2 5 230 371

4 0.5 2 231 372

2 0.2 1 232 373

4 0.4 1 233 374

2.5 0.3 1 234 375

3 4 25 235 376

3 0.1 1 236 377

4 2 3 237 378

2 0.7 2 238 379

2 0.6 15 239 380

6 8 240 381

2 1 2 241 382

3 1 3 242 383

2 0.5 2 243 384

3 2 5 244 385

3 1 2 245 386

3 1 1 246 387

2 1 1 247 388

3 0.4 5 248 389

3 0.2 1 249 390

2 0.8 5 250 391

1 0.9 3 251 392

4 1 1 252 393

4 0.6 1 253 394

4 2 25 254 395

2 1 5 255 396

2 0.7 5 256 397

1 0.6 4 258 399

14 9 259 400

8 0.3 2 260 401

6 0.3 2 261 402

14 0.4 1 262 403

1 0.2 1 263 404

3 0.6 5 264 405

5 1 5 265 406

3 11 266 407

3 2 267 408

4 2 268 409

3 1 9999 269 410

0.9 0.1 >5 270 411

2 1 271 412

3 2 3 272 413

2 2 3 273 414

3 1 1 274 415

3 1 3 275 416

3 0.6 1 276 417

3 1 1 277 418

3 0.9 2 278 419

2 1 5 279 420

3 0.7 1 280 421

4 0.6 1 281 422

<0.05 0.9 5 282 423

0.5 1 3 283a 424b

2 0.4 1 283b 424c

3 0.8 3 284 425

2 0.6 5 285 426

2 1 10 286 427

0.6 2 1 287 428

0.7 0.7 1 288 429

4 0.9 1 289 430

5 0.7 1 290 431

5 5 291 432

2 1 3 292 432

2 0.6 1 293 434

4 0.6 2 294 435

3 0.6 1 295 436

5 0.8 5 296 437

3 0.4 1 297 438

5 0.6 1 298 439

3 0.4 1 299 440

4 0.1 2 300 441

2 0.8 2 301 442

17 0.4 1 302 443

303 444

304 445

16 6 305 446

21 7 307 448

3 0.2 2 308 449

1 6 309 450

3 2 310 451

4 0.2 3 311 452

3 0.3 2 312 453

9999 37 313 454

4 2 5 314 455

4 0.7 1 315 456

3 0.4 8888 316 457

9999 9999 317 458

3 0.3 2 318 459

4 0.3 1 319 460

3 1 1 320 461

1.4 0.3 1 321 462

4 0.3 1 322 463

12 6 323 464

4 11 324 465

2 9999 9999 325 466

3 2 1 326 467

4 0.4 2 327 468

2 8 <1 426 571

4 11 427 572

1.5 5 5 428 573

7 0.4 1 429 574

13 0.7 3 430 575

2 0.2 1 431 576

5 6 432 577

2 0.5 2 433 578

0.6 0.1 1 434 579

2 0.5 1 435 580

4 0.3 <1 436 587

5 0.8 2 437 590

2 2 3 438 591

4 0.3 <1 439 592

5 0.4 <1

Assay Example 2 Antineoplastic Effects of Histone Deacetylase InhibitorSon Human Tumor Xenografts In Vivo

Eight to ten week old female BALB/c nude mice (Taconic Labs, GreatBarrington, N.Y.) were injected subcutaneously in the flank area with2×10⁶ preconditioned HCT116 human colorectal carcionoma cells.Preconditioning of these cells was done by a minimum of threeconsecutive tumor transplantations in the same train of nude mice.Subsequently, tumor fragments of approximately 30 mgs were excised andimplanted subcutaneously in mice, in the left flank area, under Foreneanesthesia (Abbott Labs, Geneve, Switzerland). When the tumors reached amean volume of 100 mm³, the mice were treated intravenously,subcutaneously, or intraperitoneally by daily injection, with a solutionof the histone deacetylase inhibitor in an appropriate vehicle, such asPBS, DMSO/water, or Tween 80/water, at a starting dose of 10 mg/kg. Theoptimal dose of the HDAC inhibitor was established by dose responseexperiments according to standard protocols. Tumor volume was calculatedevery second day post infusion according to standard methods (e.g.,Meyer et al., Int. J. Cancer 43:851-856 (1989). Treatment with the HDACinhibitors according to the invention caused a significant reduction intumor weight and volume relative to controls treated with vehicle only(i.e., no HDAC inhibitor). In addition, the level of histone acetylationwhen measured was significantly elevated relative to controls. Data forselected compounds are presented in Table 6. FIG. 1 shows the fullexperimental results for compound 106, which inhibits tumor growth by80%. FIGS. 2-10 show the results of additional compounds tested.

TABLE 6 Antitumor Activity in HCT 116 Colorectal Tumor Model In VivoCompound % Inhibition of Tumor Growth 106 80^(a) 126 62^(b) 9 51^(b) 8730^(b) 157 66^(a) 167 58^(a) 15 26^(b) 168 26^(b) 16 50^(b) 154 23^(a)98 52^(a) ^(a)20 mg/kg i.p. ^(b)40 mg/kg i.p.

TABLE 7 Antineoplastic Effects Of Histone Deacetylase Inhibitors On NudeMice Xenograft Models % Inhibition Of Tumor Growth cpd A 549 (p.o.) SW48(p.o.) A 549 (i.p.) HCT 116 (i.p.) SW 48 (i.p.) 106 40% (70 mg/kg) 16%(60 mg/kg) — — — 164 42% (70 mg/kg) 62% (60 mg/kg) — 37% (20 mg/kg) 99%(25 mg/kg) 228 45% (70 mg/kg) 25% (60 mg/kg) 64% (20 mg/kg) 45% (20mg/kg) 68% (20 mg/kg)  424b 67% (50 mg/kg) 78% (30 mg/kg) 60% (50 mg/kg)77% (75 mg/kg) 68% (25 mg/kg)

Assay Example 3 Combined Antineoplastic Effect of Histone DeacetylaseInhibitors and Histone Deacetylase Antisense Oligonucleotides on TumorCells In Vivo

The purpose of this example is to illustrate the ability of the combineduse of a histone deacetylase inhibitor of the invention and a histonedeacetylase antisense oligonucleotide to enhance inhibition of tumorgrowth in a mammal. Preferably, the antisense oligonucleotide and theHDAC inhibitor inhibit the expression and activity of the same histonedeacetylase.

As described in Example 126, mice bearing implanted HCT116 tumors (meanvolume 100 mm³) are treated daily with saline preparations containingfrom about 0.1 mg to about 30 mg per kg body weight of histonedeacetylase antisense oligonucleotide. A second group of mice is treateddaily with pharmaceutically acceptable preparations containing fromabout 0.01 mg to about 5 mg per kg body weight of HDAC inhibitor.

Some mice receive both the antisense oligonucleotide and the HDACinhibitor. Of these mice, one group may receive the antisenseoligonucleotide and the HDAC inhibitor simultaneously intravenously viathe tail vein. Another group may receive the antisense oligonucleotidevia the tail vein, and the HDAC inhibitor subcutaneously. Yet anothergroup may receive both the antisense oligonucleotide and the HDACinhibitor subcutaneously. Control groups of mice are similarlyestablished which receive no treatment (e.g., saline only), a mismatchantisense oligonucleotide only, a control compound that does not inhibithistone deacetylase activity, and a mismatch antisense oligonucleotidewith a control compound.

Tumor volume is measured with calipers. Treatment with the antisenseoligonucleotide plus the histone deacetylase protein inhibitor accordingto the invention causes a significant reduction in tumor weight andvolume relative to controls.

1. A compound of structural formula (2a):

or a pharmaceutically acceptable salt thereof, wherein Ar^(a) is phenylor thienyl; R⁶ is H, or C₁-C₆-alkyl; Y and Z are —CH═; W is(V′-L⁴)_(t)-V-L³-; L³ is a direct bond, —C₁-C₆-hydrocarbyl,—(C₁-C₃-hydrocarbyl)_(m1)-X′—(C₁-C₃-hydrocarbyl)_(m2),—NH—(C₀-C₃-hydrocarbyl), (C₁-C₃- hydrocarbyl)-NH—, or—NH—(C₁-C₃-hydrocarbyl)-NH—; m1 and m2 are independently 0 or 1; X′ is—N(R²¹)—, —C(O)N(R²¹)—, N(R²¹)C(O)—, —O—, or —S—;  R²¹ is —H,V″—(C₁-C₆-hydrocarbyl)_(c); L⁴ is(C₁-C₆-hydrocarbyl)_(a)-M-(C₁-C₆-hydrocarbyl)_(b); a and b areindependently 0 or 1; M is —NH—, —NHC(O)—, —C(O)NH—, —C(O)—, —SO₂—,—NHSO₂—, or —SO₂NH— V, V′, and V″ are independently selected fromcycloalkyl, heterocyclyl, aryl, and heteroaryl; t is 0 or 1; or W, theannular C to which it is bound, and Y together form a monocycliccycloalkyl, heterocyclyl, aryl, or heteroaryl; and wherein the A andAr^(a) rings are optionally further substituted with from 1 to 3substituents independently selected from methyl, hydroxy, methoxy, halo,and amino.
 2. The compound according to claim 1 wherein: R⁶ is H; W isV-L³-; L³ is —NH—CH— or —CH—NH—; V is phenyl optionally substituted withfrom 1 to 3 moieties independently selected from halo, hydroxy,C₁-C₆-hydrocarbyl, C₁-C₆-hydrocarbyl-oxy or -thio (particularly methoxyor methylthio), wherein each of the hydrocarbyl moieties are optionallysubstituted with one or more moieties independently selected from halo,nitroso, amino, sulfonamido, and cyano; and Ar^(a) is phenyl and theamino moieties to which it is bound are ortho to each other.
 3. Thecompound according to claim 1 wherein V is an optionally substitutedring moiety selected from the group consisting of the following:


4. The compound according to claim 1 wherein W is selected from thegroup consisting of the following:


5. The compound according to claim 1 wherein the A and Ar^(a) rings arenot further substituted.
 6. The compound according to claim 1 selectedfrom the group consisting of the following combinations, in which,unless expressly displayed otherwise, Ar^(a) is phenyl: Cpd W Y Z R⁶ 481

CH CH H, 484

492

CH CH H, 493

CH CH H, 494

CH CH H, 495

CH CH H, 496

CH CH H, 497

CH CH H, 498

CH CH H, 499

CH CH H, 500

CH CH H, 501

CH CH H, 502

CH CH H, 503

CH CH H, 504

CH CH H, 505

CH CH H, 506

CH CH H, 507

CH CH H, 508

CH CH H, 509

CH CH H, 510

CH CH H, 511

CH CH H, 517

CH CH CH₃, 518

CH CH CH₃, 519

CH CH H, 520

CH CH H, 523

CH CH H, 526

CH CH H, 527

CH CH H, 528

CH CH H, 529

CH CH H, 530

CH CH H, 531

CH CH H, 532

CH CH H, 533

CH CH H, 534

CH CH H, 535

CH CH H, 536

CH CH H, 537

CH CH H, 538

CH CH H, 539

CH CH H, 540

CH CH H, 541

CH CH H, 542

CH CH H, 543

CH CH H, 544

CH CH H, 545

CH CH H, 546

CH CH H, 547

CH CH H, 548

CH CH H, 549

CH CH H, 550

CH CH H, 551

CH CH H, 552

CH CH H, 553

CH CH H, 554

CH CH H, 555

CH CH H, 556

CH CH H, 557

CH CH H, 558

CH CH H, 559

CH CH H, 560

561

562

CH CH H, 563

CH CH H, 564

565

CH CH H, 566

CH CH H, 567

568

and 570


7. The compound according to claim 6 wherein the amide nitrogen and theamino nitrogen bound to Ar^(a) are ortho to each other.
 8. The compoundof formula (3b):

or pharmaceutically acceptable salt thereof, wherein Y and Z are CH andW is selected from the group consisting of:

F,

and


9. The compound according to claim 8 wherein Y, Z and W are one of thefollowing combinations Cpd W Y Z 164

CH CH, 166

CH CH, 169

CH CH, 170

CH CH, 172

CH CH, 179

CH CH, 180

CH CH, 181

CH CH, 182

CH CH, or 183

CH CH.


10. The compound according to claim 8 wherein Y, Z and W are one of thefollowing combinations Cpd W Y Z 187

CH CH, 188

CH CH, 189

CH CH, 190

CH CH, 193

CH CH, 194

CH CH, 195

CH CH, 196

CH CH, 320

CH CH, 321

CH CH, 322

CH CH, 323

CH CH, 325

CH CH, 326

CH CH, 327

CH CH, 328

CH CH, 329

CH CH, 330

CH CH, 331

CH CH, 332

CH CH, 333

CH CH, 334

CH CH, 335

CH CH, 336

CH CH, 337

CH CH, 338

CH CH, 339

CH CH, 340

CH CH, 341

CH CH, 342

CH CH, 343

CH CH, 344

CH CH, 345

CH CH, 346

CH CH, 347

CH CH, 348

CH CH, 349

CH CH, 350

CH CH, 351

CH CH, 356

CH CH, 357

CH CH, 358

CH CH, 359

CH CH, 360

CH CH, 361

CH CH, 362

CH CH, 363

CH CH, 364

CH CH, 365

CH CH, 366

CH CH, 368

CH CH, 369

CH CH, 370

CH CH, 375

CH CH, 377

CH CH, 378

CH CH, 379

CH CH, 381

CH CH, 382

CH CH, 383

CH CH, 384

CH CH, 385

CH CH, 386

CH CH, 387

CH CH, 388

CH CH, 389

CH CH, 390

CH CH, 391

CH CH, 392

CH CH, 393

CH CH, 394

CH CH, 395

CH CH, 396

CH CH, 397

CH CH, 399

CH CH, 400

CH CH, 401

CH CH, 402

CH CH, 403

CH CH, 404

CH CH, 405

CH CH, 406

CH CH, 407

CH CH, 408

CH CH, 409

CH CH, 410

CH CH, 411

CH CH, 412

CH CH, 413

CH CH, 414

CH CH, 415

CH CH, 416

CH CH, 417

CH CH, 418

CH CH, 419

CH CH, 420

CH CH, 421

CH CH, 422

CH CH, 423

CH CH,  424b

CH CH, 425

CH CH, 426

CH CH, 427

CH CH, 428

CH CH, 429

CH CH, 430

CH CH, 431

CH CH, 432

CH CH, 433

CH CH, 434

CH CH, 435

CH CH, 436

CH CH, 437

CH CH, 438

CH CH, 439

CH CH, 440

CH CH, 441

CH CH, 442

CH CH, 443

CH CH, 444

CH CH, 447

CH CH, 448

CH CH, 449

CH CH, 450

CH CH, 451 F CH CH, 452

CH CH, 453

454

455

CH CH, 456

CH CH, 457

458

CH CH, 459

CH CH, 461

CH CH, 462

CH CH, 465

CH CH, 466

CH CH, 467

CH CH, or 468

CH CH.


11. A compound selected from the group consisting of the following andtheir pharmaceutically acceptable salts:


12. A histone deacetylase inhibitor selected from the group consistingof the following compounds and their pharmaceutically acceptable salts:

N-(2-Amino-phenyl)-4-(quinolin-2- ylsulfanylmethyl)-benzamide,N-(2-Amino-phenyl)-4-(4,6-dimethyl-pyrimidin-2-ylsulfanylmethyl)-benzamide,N-(2-Amino-phenyl)-4-(4-trifluoromethyl-pyrimidin-2-ylsulfanylmethyl)-benzamide, Biphenyl-4,4′-dicarboxylic acidbis-[(2- amino-phenyl)-amide], N-(2-Amino-phenyl)-4-(2,4-dioxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3- ylmethyl)-benzamide,N-(2-Amino-phenyl)-4-[bis-(3- trifluoromethoxy-benzyl)-amino]-benzamide, and N-(2-Amino-phenyl)-3-(4-{[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-ethylamino]-methyl}-phenyl)- acrylamide.


13. A composition comprising a compound according to any one of claim1-7 or 8-10 and a pharmaceutically acceptable carrier.
 14. A method oftreating or inhibiting colon cancer, the method comprising administeringto a patient in need thereof a effective amount of a compound accordingto any one of claims 1-7 and 8-12, or a pharmaceutical compositionthereof.
 15. A method of treating or inhibiting colon cancer, the methodcomprising administering to a patient in need thereof an effectiveamount of a compound of structural formula (2a):

or a pharmaceutically acceptable salt thereof, said compound optionallyadministered together with a pharmaceutically acceptable carrier,wherein Ar^(a) is phenyl or thienyl; R⁶ is H, or C₁-C₆-alkyl; Y and Zare —CH═; W is halo; or W, the annular C to which it is bound, and Ytogether form a monocyclic cycloalkyl, heterocyclyl, aryl, orheteroaryl; and wherein the A and Ar^(a) rings are optionally furthersubstituted with from 1 to 3 substituents independently selected frommethyl, hydroxy, methoxy, halo, and amino.